Tie-2 modulators and methods of use

ABSTRACT

The present invention provides compounds for modulating protein kinase enzymatic activity for modulating cellular activities such as proliferation, differentiation, programmed cell death, migration and chemoinvasion. Compounds of the invention inhibit, regulate and/or modulate kinases, particularly Tie-2. Methods of using the compounds and pharmaceutical compositions thereof to treat kinase-dependent diseases and conditions are also an aspect of the invention.

This application is a the National Stage of International ApplicationPCT/US2004/008579, filed Mar. 19, 2004, which claims the benefit of U.S.Provisional Application No. 60/456,565, filed Mar. 19, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to compounds for modulating protein kinaseenzymatic activity for modulating cellular activities such asproliferation, differentiation, programmed cell death, migration andchemoinvasion. Even more specifically, the invention relates tocompounds that inhibit, regulate and/or modulate kinases, particularlyTie-2. Kinase receptor signal transduction pathways related to thechanges in cellular activities as mentioned above are modulated usingcompounds of the invention. Methods of using the compounds to treatkinase-dependent diseases and conditions are also an aspect of theinvention.

2. Summary of Related Art

Improvements in the specificity of agents used to treat cancer is ofconsiderable interest because of the therapeutic benefits which would berealized if the side effects associated with the administration of theseagents could be reduced. Traditionally, dramatic improvements in thetreatment of cancer are associated with identification of therapeuticagents acting through novel mechanisms.

Protein kinases are enzymes that catalyze the phosphorylation ofproteins, in particular, hydroxy groups on tyrosine, serine andthreonine residues of proteins. The consequences of this seeminglysimple activity are staggering; cell differentiation and proliferation;i.e., virtually all aspects of cell life in one-way or another depend onprotein kinase activity. Furthermore, abnormal protein kinase activityhas been related to a host of disorders, ranging from relativelynon-life threatening diseases such as psoriasis to extremely virulentdiseases such as glioblastoma (brain cancer).

Protein kinases can be categorized as receptor type or non-receptortype. Receptor-type tyrosine kinases have an extracellular, atransmembrane, and an intracellular portion, while non-receptor typetyrosine kinases are wholly intracellular.

Receptor-type tyrosine kinases are comprised of a large number oftransmembrane receptors with diverse biological activity. In fact, about20 different subfamilies of receptor-type tyrosine kinases have beenidentified. One tyrosine kinase subfamily, designated the HER subfamily,is comprised of EGFR (HER1), HER2, HER3, and HER4. Ligands of thissubfamily of receptors identified so far include epithelial growthfactor, TGF-alpha, amphiregulin, HB-EGF, betacellulin and heregulin.Another subfamily of these receptor-type tyrosine kinases is the insulinsubfamily, which includes INS-R, IGF-IR, and IR-R. The PDGF subfamilyincludes the PDGF-alpha and beta receptors, CSFIR, c-kit and FLK-II.Then there is the FLK family, which is comprised of the kinase insertdomain receptor (KDR), fetal liver kinase-1 (FLK-1), fetal liverkinase-4 (FLK-4) and the fms-like tyrosine kinase-1 (flt-1). The PDGFand FLK families are usually considered together due to the similaritiesof the two groups. For a detailed discussion of the receptor-typetyrosine kinases, see Plowman et al., DN&P 7(6): 334-339, 1994, which ishereby incorporated by reference.

The non-receptor type of tyrosine kinases is also comprised of numeroussubfamilies, including Src, Frk, Btk, Csk, Abl, Zap70, Fes/Fps, Fak,Jak, Ack, and LIMK. Each of these subfamilies is further sub-dividedinto varying receptors. For example, the Src subfamily is one of thelargest and includes Src, Yes, Fyn, Lyn, Lck, Blk, Hck, Fgr, and Yrk.The Src subfamily of enzymes has been linked to oncogenesis. For a moredetailed discussion of the non-receptor type of tyrosine kinases, seeBolen, Oncogene, 8:2025-2031 (1993), which is hereby incorporated byreference.

Since protein kinases and their ligands play critical roles in variouscellular activities, deregulation of protein kinase enzymatic activitycan lead to altered cellular properties, such as uncontrolled cellgrowth associated with cancer. In addition to oncological indications,altered kinase signaling is implicated in numerous other pathologicaldiseases. These include, but are not limited to: immunologicaldisorders, cardiovascular diseases, inflammatory diseases, anddegenerative diseases. Therefore, both receptor and non-receptor proteinkinases are attractive targets for small molecule drug discovery.

One particularly attractive goal for therapeutic use of kinasemodulation relates to oncological indications. For example, modulationof protein kinase activity for the treatment of cancer has beendemonstrated successfully with the FDA approval of Gleevec® (imatinibmesylate, produced by Novartis Pharmaceutical Corporation of EastHanover, N.J.) for the treatment of Chronic Myeloid Leukemia (CML) andgastrointestinal stroma cancers. Gleevec is a selective Abl kinaseinhibitor.

Modulation (particularly inhibition) of cell proliferation andangiogenesis, two key cellular processes needed for tumor growth andsurvival (Matter A. Drug Disc Technol 2001 6, 1005-1024), is anattractive goal for development of small-molecule drugs. Anti-angiogenictherapy represents a potentially important approach for the treatment ofsolid tumors and other diseases associated with dysregulatedvascularization, including ischemic coronary artery disease, diabeticretinopathy, psoriasis and rheumatoid arthritis. As well, cellantiproliferative agents are desirable to slow or stop the growth oftumors.

One particularly attractive target for small-molecule modulation, withrespect to antiangiogenic and antiproliferative activity is Tie-2. Tie-2(also called TEK) is a member of the receptor tyrosine kinase (RTK)family, which is expressed primarily in endothelial cells and earlyhemopoietic cells, and plays a critical role in the processes ofvasculogenesis and angiogenesis. As such, Tie-2 has been shown toparticipate in endothelial cell migration, sprouting, survival andperiendothelial cell recruitment during angiogenesis.

The angiopoietin family of growth factors regulates Tie-2 activitythrough a combination of agonistic and antagonistic extracellularligands. Binding of the ligands, Angiopoietin-1 (Ang-1) or Ang-4 byTie-2 induces autophosphorylation resulting in an increase of receptordependent signaling, while binding to Ang-2 and Ang-3 results in downregulation of receptor activity. Ang-1 signaling through Tie-2facilitates later stages of vascular development by modulatingcell-cell, and cell-matrix interactions, resulting in the survival andstabilization of newly formed blood vessels.

Tumor growth progression requires the recruitment of new blood vesselsinto the tumor from preexisting vessels. Accordingly, Tie-2 expressionhas been demonstrated on a wide variety of tumor types includingovarian, breast, renal, prostate, lung, thyroid, myeloid leukemia,hemangiomas, melanomas, astrocytomas, and glioblastomas. Tie-2activation has also been linked to venous malformations (VM), the mostcommon form of vascular morphogenesis in humans. As well, an activatingmutation in the kinase domain of Tie-2 occurs in multiple families whoexhibit a dominantly inherited form of VM. Tie-2 has been linked tomultiple cancer types, including ovarian, breast, renal, prostate, lung,thyroid, myeloid leukemia, hemangiomas, melanomas, astrocytomas, andglioblastomas (See: Shirkawa et al Int J Cancer 2002 Jun. 20;99(6):821-8; Tanka et al Clin Cancer Res 2002 May; 8(5):1125-31;Mitsutake et al Thyroid 2002 February; 12(2):95-9; Muller et al Leuk Res2002 February; 26(2): 163-8; Yu et al Am J Pathol 2001 December;159(6):2271-80; Pomyje et al Melanoma Res 2001 December; 11(6):639-43;Harris et al Clin Cancer Res 2001 July; 7(7):1992-7; Wrumback et alAnticancer Res 2000 November-December; 20(6D):5217-20; Ding et alDeuro-oncol 2001 January; 3(1):1-10; Takahama et al Clin Cancer Res 1999September; 5(9):2506-10; Stratmann et al Am J Pathol 1998 November;153(5):1549-66; and, Kukk et al Br J Haematol 1997 July; 98(1):195-203).Additionally, activation of Tie-2 has been linked to the vasculardysmorphogenesis syndrome, venous malformation (See: Vikkula et al Cell1996 December; 87(1):1181-1190). Thus modulation of Tie-2 is desirableas a means to treat cancer and cancer-related disease.

Accordingly, the identification of small-molecule compounds thatspecifically inhibit, regulate and/or modulate the signal transductionof kinases, particularly Tie-2, is desirable as a means to treat orprevent disease states associated with abnormal cell proliferation andangiogenesis, and is an object of this invention.

SUMMARY OF THE INVENTION

The present invention provides compounds for modulating kinase activityand methods of treating diseases mediated by kinase activity, inparticular Tie-2, utilizing the compounds and pharmaceuticalcompositions thereof. Diseases mediated by kinase activity are fromherein referred to as “kinase-dependent diseases or conditions” (seedefinition in detailed description of invention below). Inhibitors thatare selective for a Tie-2 are included in this invention.

In another aspect, the invention provides methods of screening formodulators of kinase activity. The methods comprise combining acomposition of the invention, a kinase, and at least one candidate agentand determining the effect of the candidate agent on the kinaseactivity.

In yet another aspect, the invention also provides pharmaceutical kitscomprising one or more containers filled with one or more of theingredients of pharmaceutical compounds and/or compositions of thepresent invention, including, one or more kinase enzyme activitymodulators as described herein. Such kits can also include, for example,other compounds and/or compositions (e.g., diluents, permeationenhancers, lubricants, and the like), a device(s) for administering thecompounds and/or compositions, and written instructions in a formprescribed by a governmental agency regulating the manufacture, use orsale of pharmaceuticals or biological products, which instructions canalso reflects approval by the agency of manufacture, use or sale forhuman administration.

In still yet another aspect, the invention also provides a diagnosticagent comprising a compound of the invention and, optionally,pharmaceutically acceptable adjuvants and excipients.

These and other features and advantages of the present invention will bedescribed in more detail below.

DETAILED DESCRIPTION OF THE INVENTION

The compositions of the invention are used to treat diseases associatedwith abnormal and or unregulated cellular activities. Disease stateswhich can be treated by the methods and compositions provided hereininclude, but are not limited to, cancer (further discussed below),immunological disorders such as rheumatoid arthritis, graft-hostdiseases, multiple sclerosis, psoriasis; cardiovascular diseases such asatherosclerosis, myocardioinfarction, ischemia, pulmonary hypertension,stroke and restenosis; other inflammatory and degenerative diseases suchas interbowel diseases, osteoarthritus, macular degeneration, diabeticretinopathy.

It is appreciated that in some cases the cells may not be in a hyper- orhypo-proliferative and/or migratory state (abnormal state) and stillrequire treatment. For example, during wound healing, the cells may beproliferating “normally,” but proliferation and migration enhancementmay be desired. Alternatively, reduction in “normal” cell proliferationand/or migration rate may be desired.

The present invention comprises a compound for modulating kinaseactivity, particularly Tie-2, of Formula I,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,wherein,Ar is a five- to six-membered aromatic ring system containing betweenone and three heteroatoms, said five- to six-membered aromatic ringsystem substituted with —X and —Y-L-Z, in an ortho relationship to eachother, and said five- to six-membered aromatic ring system optionallysubstituted with up to four R¹;each R¹ is independently selected from —H, halogen, —CN, —NO₂, —OR³,—N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, —OC(O)R³, optionally substitutedlower alkyl, optionally substituted aryl, optionally substituted lowerarylalkyl, optionally substituted heterocyclyl, and optionallysubstituted lower heterocyclylalkyl;optionally two of R¹, together with the atoms to which they areattached, form a first ring system fused with Ar, said first ring systemsubstituted with zero to three additional of R¹;X is selected from the following six formulae:

wherein,W is selected from —C(R²)(R²)—, —N(R⁴)—, —S(O)₀₋₂—, and —O—;n=1 or 2;p=0 or 1;q is 1 to 3;M is —OR³ or —N(R³)R⁴;each R² is independently selected from —H, halogen, oxo, —CN, —NH₂,—NO₂, —OR³, —N(R³)R³, —N(R³)R⁵, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³,—C(O)N(R³)R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —N(R³)C(O)N(R³)R³,—C(O)R³, —OC(O)R³, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted lower arylalkyl, optionallysubstituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl;two of R², together with the atoms to which they are attached, can forman optionally substituted three- to seven-membered ring system;each R³ is independently selected from —H, optionally substituted loweralkyl, optionally substituted aryl, optionally substituted lowerarylalkyl, optionally substituted heterocyclyl, and optionallysubstituted lower heterocyclylalkyl; ortwo of R³, when taken together with a common nitrogen to which they areattached, form an optionally substituted five- to seven-memberedheterocyclyl ring, said optionally substituted five- to seven-memberedheterocyclyl ring optionally containing at least one additionalheteroatom selected from N, O, S, and P;each R⁴ is independently selected from R³, —SO₂R³, —SO₂N(R³)R³, —CO₂R³,—C(O)N(R³)R³, and —C(O)R³;Y is selected from —CH₂—, —O—, —S(O)₀₋₂—, —N(R³)—, and absent;L is selected from —(CH₂)₁₋₃—, —(CH₂)₁₋₃N(R³)—, —(CH₂)₁₋₃O—,—(CH₂)₁₋₃S(O)₀₋₂— and absent; each of the aforementioned methylenesoptionally substituted;Z is a five- to seven-membered ring system or —R³, said five- toseven-membered ring system optionally substituted with zero to four ofR⁵; andR⁵ is selected from —H, halogen, —CN, oxo, —NO₂, —OR³, —N(R³)R⁴,—S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R, —N(R³)SO₂R³, —N(R³)C(O)R³,—N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted lower arylalkyl, optionallysubstituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl; andoptionally two of R⁵, together with the atoms to which they areattached, form a second ring system fused with said five- toseven-membered ring system, said second ring system substituted withzero to four of R⁵, hereinafter embodiment [0021].

In one example, the compound is according to embodiment [0021], havingformula II,

wherein, A and E are each independently N or —C(R¹)—; and G is selectedfrom —S(O)₀₋₂—, and —C(R¹)═C(R¹)—, hereinafter embodiment [0022].

In another example, the compound is according to embodiment [0022],wherein Ar is selected from the following formulae:

hereinafter embodiment [0023].

In another example, the compound is according to embodiment [0023],wherein —Y-L-Z is selected from the following formulae,

wherein g is zero to two; D is selected from —C(R⁵)(R⁵)—, —O—,—S(O)₀₋₂—, and —N(R⁴)—; Q is ═N— or —C(R⁵)—, T is selected from absent,—N(R³)—, —S— and —O—; and each methylene between Y and T is optionallysubstituted; provided that when both Y and T are heteroatoms then g mustbe two, hereinafter embodiment [0024].

In another example, the compound is according to embodiment [0024],wherein Y is —O— or optionally substituted —CH₂—, hereinafter embodiment[0025].

In another example, the compound is according to embodiment [0025],wherein X is selected from the following formulae:

hereinafter embodiment [0026]

In another example, the compound is according to embodiment [0026],wherein R^(4a) is selected from —SO₂R³, —SO₂N(R³)R⁴, —CO₂R³,—C(O)N(R³)R⁴, and —C(O)R³, hereinafter embodiment [0027].

In another example, the compound is according to embodiment [0027],wherein each R² is independently selected from —H or optionallysubstituted lower alkyl, hereinafter embodiment [0028].

In another example, the compound is according to embodiment [0028],wherein each R² is independently selected from —H, haloalkyl,—C₁₋₆alkyl-N(R³)R³, —C₁₋₆alkyl-OR³, —C₁₋₆alkyl-CO₂R³, and—C₁₋₆alkyl-C(O)N(R³)R³, hereinafter embodiment [0029].

In another example, the compound is according to embodiment [0029],wherein R^(4a) is —C(O)N(R³)R³ or —C(O)R³, hereinafter embodiment[0030].

In another example, the compound is according to embodiment [0030],wherein —Y-L-Z is selected from the following formulae,

wherein Y, T, and g are as described above, hereinafter embodiment[0031].

In another example, the compound is according to embodiment [0031],wherein g is one or two, hereinafter embodiment [0032].

In another example, the compound is according to embodiment [0032],wherein each R⁵ is independently selected from —H, halogen, —CN, —NH₂,—NO₂, —OR³, —N(R³)R⁴, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionallysubstituted lower alkyl, hereinafter embodiment [0033].

In another example, the compound is according to embodiment [0033],wherein —Y-L-Z is selected from the following formulae:

hereinafter embodiment [0034]

In another example, the compound is according to embodiment [0034],having formula III,

wherein J is N or CH, and B is ═N— or ═C(R⁵)—, hereinafter embodiment[0035].

In another example, the compound is according to embodiment [0035],wherein R^(3a) is selected from optionally substituted aryl, optionallysubstituted lower arylalkyl, optionally substituted heterocyclyl, andoptionally substituted lower heterocyclylalkyl, hereinafter embodiment[0036].

In another example, the compound is according to embodiment [0036],wherein R^(3a) is selected from optionally substituted aryl andoptionally substituted heteroaryl, hereinafter embodiment [0037].

In another example, the compound is according to embodiment [0037],wherein R^(3a) is optionally substituted phenyl, hereinafter embodiment[0038].

In another example, the compound is according to embodiment [0038],wherein said optionally substituted phenyl is substituted with at leastone of halogen, —CN, —CF₃, —NH₂, —NO₂, —OR³, —N(R³)R³, —S(O)₀₋₂R³,—SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³, —N(R³)C(O)R³,—N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl, and optionallysubstituted aryl, hereinafter embodiment [0039].

In another example, the compound is according to embodiment [0039],wherein said optionally substituted phenyl group is substituted with atleast one trifluoromethyl group, hereinafter embodiment [0040].

In another example, the compound is according to embodiment [0040],wherein said optionally substituted phenyl group is substituted with atleast two trifluoromethyl groups, hereinafter embodiment [0041].

In another example, the compound is according to embodiment [0039],wherein said optionally substituted phenyl group is substituted with atleast one lower alkyl group, hereinafter embodiment [0042].

In another example, the compound is according to embodiment [0039],wherein R^(3b) is —H, hereinafter embodiment [0043].

In another example, the compound is according to embodiment [0043],wherein R^(3b) is selected from R³, —H, —CO₂R³, —C(O)N(R³)R⁴, and—C(O)R³, hereinafter embodiment [0044].

In another example, the compound is according to embodiment [0044],wherein Ar is according to the formula below, hereinafter embodiment[0045].

In another example, the compound is according to embodiment [0044],wherein Ar is according to the formula below, hereinafter embodiment[0046].

In another example, the compound is according to embodiment [0044],wherein Ar is according to the formula below, hereinafter embodiment[0047].

In another example, the compound is according to embodiment [0044],wherein Ar is according to the formula below, hereinafter embodiment[0048].

In another example, the compound is according to embodiment [0044],wherein Ar is according to the formula below, hereinafter embodiment[0049]

In another example, the present invention comprises a compound formodulating kinase activity, particularly Tie-2, of Formula IV,

or a pharmaceutically acceptable salt, hydrate, or prodrug thereof,wherein, Ar is selected from the following formulae:

each R¹ is independently selected from —H, halogen, —CN, —NO₂, —OR³,—N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted lower arylalkyl,optionally substituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl;optionally two of R¹, together with the atoms to which they areattached, form a first ring system fused with Ar, said first ring systemsubstituted with zero to three additional of R¹;each R² is independently selected from —H, halogen, oxo, —CN, —NH₂,—NO₂, —OR³, —N(R³)R³, —N(R³)R⁵, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³,—C(O)N(R³)R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —N(R³)C(O)N(R³)R³,—C(O)R³, optionally substituted lower alkyl, optionally substitutedaryl, optionally substituted lower arylalkyl, optionally substitutedheterocyclyl, and optionally substituted lower heterocyclylalkyl;two of R², together with the atoms to which they are attached, can forman optionally substituted three- to seven-membered ring system;each R³ is independently selected from —H, optionally substituted loweralkyl, optionally substituted aryl, optionally substituted lowerarylalkyl, optionally substituted heterocyclyl, and optionallysubstituted lower heterocyclylalkyl; ortwo of R³, when taken together with a common nitrogen to which they areattached, form an optionally substituted five- to seven-memberedheterocyclyl ring, said optionally substituted five- to seven-memberedheterocyclyl ring optionally containing at least one additionalheteroatom selected from N, O, S, and P;each R⁴ is independently selected from R³, —SO₂R³, —SO₂N(R³)R³, —CO₂R³,—C(O)N(R³)R³, and —C(O)R³;Y is selected from optionally substituted —CH₂—, —O—, —S—, and —N(R³)—;L is selected from optionally substituted —CH₂—, —O—, —S—, —N(R³)— andabsent;provided that Y and L are not both heteroatoms;B is ═N— or ═C(H)—;at each instance, R⁵ and R⁶ are independently selected from —H, halogen,—CN, —NO₂, —OR³, —N(R³)R⁴, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substitutedlower alkyl, optionally substituted aryl, optionally substituted lowerarylalkyl, optionally substituted heterocyclyl, and optionallysubstituted lower heterocyclylalkyl; andoptionally two of R⁵, together with the atoms to which they areattached, form a ring system fused with the ring containing B accordingto formula IV, said ring system substituted with zero to two additionalof R⁵, hereinafter embodiment [0050].

In another example, the compound is according to embodiment [0050],wherein Y is —O— and L is optionally substituted —CH₂—, hereinafterembodiment [0051].

In another example, the compound is according to embodiment [0051],wherein at least one of R⁶ is optionally substituted lower alkyl,hereinafter embodiment [0052].

In another example, the compound is according to embodiment [0052],wherein said at least one optionally substituted lower alkyl is meta- tothe piperazine urea function as depicted in formula IV, hereinafterembodiment [0053].

In another example, the compound is according to embodiment [0053],wherein R^(4a) is selected from R³, —H, —CO₂R³, —C(O)N(R³)R⁴, and—C(O)R³, hereinafter embodiment [0054].

In another example, the compound is according to embodiment [0054],wherein R^(4a) is selected from —H, —CO₂R³, —C(O)N(R³)R⁴, and —C(O)R³,hereinafter embodiment [0055].

In another example, the compound is according to embodiment [0055],wherein —Y-L- is —OCH₂—, hereinafter embodiment [0056].

In another example, the compound is according to embodiment [0056],wherein Ar is according to the formula below, hereinafter embodiment[0057].

In another example, the compound is according to embodiment [0056],wherein Ar is according to the formula below, hereinafter embodiment[0058].

In another example, the compound is according to embodiment [0056],wherein Ar is according to the formula below, hereinafter embodiment[0059].

In another example, the compound is according to embodiment [0056],wherein Ar is according to the formula below, hereinafter embodiment[0060].

In another example, the compound is according to embodiment [0056],wherein Ar is according to the formula below, hereinafter embodiment[0061].

In another example, the compound is according to embodiment [0021],selected from Table 1, hereinafter embodiment [0062].

TABLE 1 1 N-[(1R,2S)-2-phenylcyclopropyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

2 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

3 N-[4-chloro-3-(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

4 N-[4-(1-methylethyl)phenyl]-4-{4- [(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide

5 N-(3-bromophenyl)-4-{4-[(pyridin-4- ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

6 N-[3-(methylthio)phenyl]-4-{4- [(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide

7 N-(3-ethylphenyl)-4-{4-[(pyridin-4- ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

8 N-(3,5-dimethylphenyl)-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- yl}piperazine-1-carboxamide

9 N-[3-trifluoromethylphenyl]-4-{4- [(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide

10 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-methylquinolin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1- carboxamide

11 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4- ({[3-(dimethylamino)phenyl]methyl}oxy)- 1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

12 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-(1H-indol-5-yloxy)-1,2,5-thiadiazol-3- yl]piperazine-1-carboxamide

13 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(3-thienylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

14 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-morpholin-4-ylethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

15 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[2-(1H-imidazol-1-yl)ethyl]oxy}-1,2,5- thiadiazol-3-yl)piperazine-1-carboxamide

16 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(1-methylpiperidin-4-yl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

17 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[4-(methyloxy)phenyl]methyl}oxy)- 1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

18 4-[4-({[3,4- bis(methyloxy)phenyl]methyl}oxy)-1,2,5-thiadiazol-3-yl]-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1-carboxamide

19 4-{4-[(1,3-benzodioxol-5- ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

20 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(furan-3-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

21 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(tetrahydrofuran-3-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide

22 N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide

23 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}-1,4-diazepane-1-carboxamide

24 1-({[(1S,2R,5S)-5-methyl-2-(1- methylethyl)cyclohexyl]oxy}acetyl)-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine

25 5-phenyl-N-(1-{4-[(pyridin-4- ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)-1,3-oxazole-4- carboxamide

26 1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}-4-{[3-(trifluoromethyl)phenyl]acetyl}piperazine

27 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(piperidin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

28 N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperidin-4-yl)methyl]urea

29 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(3-pyridin-3-ylpropyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

30 N-[3,5-bis(trifluoromethyl)phenyl]-4- {1,1,-dioxido-4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- yl}piperazine-1-carboxamide

31 4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)- 1,2,5-thiadiazol-3-yl]-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

32 4-[({4-[4-({[3,5- bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3- yl}oxy)methyl]benzoic acid

33 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(piperidin-3-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

34 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-pyrrolidin-1-ylethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

35 4-{4-[(2-amino-2-methylpropyl)oxy]- 1,2,5-thiadiazol-3-yl}-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

36 N-[3,5-bis(trifluoromethyl)phenyl]-1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperidine-4-carboxamide

37 1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}-N-[3-(trifluoromethyl)phenyl]piperidine-4- carboxamide

38 N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2- yl}piperazine-1-carboxamide

39 4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin- 2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

40 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-piperidin-4-ylethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

41 2-methyl-4-{4-[(pyridin-4- ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

42 1-phenyl-4-{4-[(pyridin-4- ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine

43 1-[(4-methylphenyl)methyl]-4-{4- [(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine

44 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)amino]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

45 4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}-N-[3-(trifluoromethyl)phenyl]-1,4-diazepane- 1-carboxamide

46 2-methyl-1-{[2- (methyloxy)phenyl]carbonyl}-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine

47 N-[5-chloro-2-(methyloxy)phenyl]-N′-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)urea

48 N-[5-methyl-2-(methyloxy)phenyl]-N′-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)urea

49 N-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)-N′-[3-(trifluoromethyl)phenyl]urea

50 2-methyl-N-[4-(1-methylethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

51 2-methyl-N-[3-(methylthio)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

52 (2R)-N-[3,5- bis(trifluoromethyl)phenyl]-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

53 (2R)-2-methyl-4-{4-[4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

54 1-[4-(4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazin-1- yl)phenyl]ethanone

55 2-(4-{4-[(pyridin-4-ylmethyl)oxy]- 1,2,5-thiadiazol-3-yl}piperazin-1-yl)pyrimidine

56 1-[2-nitro-4-(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine

57 (2S)-N-[3,5- bis(trifluoromethyl)phenyl]-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

58 (2S)-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

59 N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-hydroxypyrazin-2-yl)piperazine-1- carboxamide

60 2-[2,5-bis(trifluoromethyl)phenyl]-N-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}pyrrolidin-3-yl)acetamide

61 1-{[2,5- bis(trifluoromethyl)phenyl]acetyl}-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]- 1,2,5-thiadiazol-3-yl}piperazine

62 N-[3,5-bis(trifluoromethyl)phenyl]-2- methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine- 1-carboxamide

63 2-methyl-4-{3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

64 N-[3,5-bis(trifluoromethyl)phenyl]-2,6- dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine- 1-carboxamide

65 2,6-dimethyl-4-{3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

66 N-(1-{3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)-N′-[3-(trifluoromethyl)phenyl]urea

67 N-[3,5-bis(trifluoromethyl)phenyl]-N′-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin- 2-yl}pyrrolidin-3-yl)urea

68 N-[3,5-bis(trifluoromethyl)phenyl]-2,6- dimethyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- yl}piperazine-1-carboxamide

69 2,6-dimethyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

70 N-[3,5-bis(trifluoromethyl)phenyl]-3- methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine- 1-carboxamide

71 3-methyl-4-{3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

72 N-[3,5-bis(trifluoromethyl)phenyl]-4- {2-[(pyridin-4-ylmethyl)oxy]phenyl}piperazine-1- carboxamide

73 4-{2-[(pyridin-4-ylmethyl)oxy]phenyl}- N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

74 N-[3,5-bis(trifluoromethyl)phenyl]-2- methyl-4-{3-[(pyridin-4-ylmethyl)oxy]quinoxalin-2- yl}piperazine-1-carboxamide

75 N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2- yl}-1,4-diazepane-1-carboxamide

76 2-methyl-4-{3-[(pyridin-4- ylmethyl)oxy]quinoxalin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

77 4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]- 1,4-diazepane-1-carboxamide

78 N-[3,5-bis(trifluoromethyl)phenyl]-2,5- dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine- 1-carboxamide

79 2,5-dimethyl-4-{3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

80 (2S)-N-[3,5- bis(trifluoromethyl)phenyl]-2-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2- yl}piperazine-1-carboxamide

81 (2S)-2-methyl-4-{3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

82 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-fluoropyridin-4-yl)methyl]oxy}- 1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

83 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-chloropyridin-4-yl)methyl]oxy}- 1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

84 N-[3,5-bis(trifluoromethyl)phenyl]-4-(3- {[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine- 1-carboxamide

85 N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(2,3,5,6-tetrafluoropyridin-4- yl)amino]methyl}phenyl)piperazine-1-carboxamide

86 N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(3-chloro-2,5,6-trifluoropyridin-4-yl)amino]methyl}phenyl)piperazine-1- carboxamide

87 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-bromopyridin-4-yl)methyl]oxy}- 1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

88 N-[3,5-bis(trifluoromethyl)phenyl]-4-(3- {[(2-bromopyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine- 1-carboxamide

89 N-[3,5-bis(trifluoromethyl)phenyl]-4-(3- {[(2-fluoropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine- 1-carboxamide

90 N-[3,5-bis(trifluoromethyl)phenyl]-4- {5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine- 1-carboxamide

91 4-{5,6-dicyano-3-[(pyridin-4- ylmethyl)oxy]pyrazin-2-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

92 N-(3-ethylphenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine- 1-carboxamide

93 N-(3-ethylphenyl)-2-methyl-4-{3- [(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide

94 N-(3-ethylphenyl)-2,6-dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2- yl}piperazine-1-carboxamide

95 N-(3-ethylphenyl)-2-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]quinoxalin-2- yl}piperazine-1-carboxamide

96 N-[3,5-bis(trifluoromethyl)phenyl]-4-[3-(2-pyridin-4-ylethyl)pyrazin-2- yl]piperazine-1-carboxamide

97 N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2- yl}piperazine-1-carboxamide

98 N-[3,5-bis(trifluoromethyl)phenyl]-4- {2-[(pyridin-4-yloxy)methyl]phenyl}piperazine-1- carboxamide

99 4-(4-{[(2-aminopyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

100 1,1-dimethylethyl {4-[({4-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

101 methyl {4-[({4-[4-({[3,5- bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

102 4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}pyridin-2-amine

103 N-(4-chlorophenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine- 1-carboxamide

104 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

105 N-(3-chlorophenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine- 1-carboxamide

106 4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}-N-propylpyridin-2- amine

107 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(propylamino)pyridin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

108 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(methylamino)pyrimidin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

109 N-methyl-4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}pyridin-2- amine

110 N-ethyl-4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}pyridin-2- amine

111 N-butyl-4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}pyridin-2- amine

112 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(methylamino)pyridin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

113 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4- ({[2-(ethylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3- yl]piperazine-1-carboxamide

114 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4- ({[2-(butylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3- yl]piperazine-1-carboxamide

115 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(phenylmethyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3- yl}piperazine-1-carboxamide

116 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(1-methylethyl)amino]pyrimidin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

117 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(phenylmethyl)amino]pyrimidin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

118 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(phenylamino)pyrimidin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

119 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4- {[2-{[2-(dimethylamino)ethyl]amino}pyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- yl)piperazine-1-carboxamide

120 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4- {[(2-{[2-(dimethylamino)ethyl]amino}pyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

121 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(ethylamino)pyrimidin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

122 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(propylamino)pyrimidin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

123 N-[3,5-bis(triflouromethyl)phenyl]-4-[4-({[2-(cyclopropylamino)pyrimidin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

124 4-[4-({[2-(acetylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]- N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

125 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(phenylcarbonyl)amino]pyridin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

126 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(phenylcarbonyl)amino]pyrimidin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

127 4-{4-[({2- [bis(phenylcarbonyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}- N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

128 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(cyclopentylamino)pyrimidin-4- yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

129 4-[4-({[2-(acetylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]- N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

130 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)amino]pyridin-4-yl}methyl)oxy]- 1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

131 methyl {4-[({4-[4-({[3,5- bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3- yl}oxy)methyl]pyrimidin-2-yl}carbamate

132 4-(4-{[(2-aminopyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

133 methyl [4-({[4-(4-{[(3- ethylphenyl)amino]carbonyl}piperazin-1-yl)-1,2,5-thiadiazol-3- yl]oxy}methyl)pyridin-2-yl]carbamate

134 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-cyanopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1- carboxamide

135 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

136 4-[({4-[4-({[3,5- bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3- yl}oxy)methyl]pyrimidine-2-carboxamide

137 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4- ({[2-(butyloxy)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3- yl]piperazine-1-carboxamide

138 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyrimidin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine-1-carboxamide

139 4-[({4-[4-({[3,5- bis(tirfluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridine-2-carboxylic acid

140 2-pyrrolidin-1-ylethyl {4-[({4-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

141 2-morpholin-4-ylethyl {4-[({4-[4- ({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

142 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

143 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[(1-methylpiperidin-3- yl)carbonyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- yl)piperazine-1-carboxamide

144 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethylphenyl)piperazine-1-carboxamide

145 2-(4-methylpiperazin-1-yl)ethyl {4-[({4- [4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

146 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4- {[(2-{[(1-ethylpiperidin-4-yl)carbonyl]amino}pyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

147 4-(4-{[(2-aminopyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-{3- [(trifluoromethyl)thio]phenyl}piperazine- 1-carboxamide

148 4-({[4-(4-{[3,5- bis(trifluoromethyl)phenyl]sulfonyl}pipe-razin-1-yl)-1,2,5-thiadiazol-3- yl]oxy}methyl)pyridin-2-amine

149 4-(4-{[(2-aminopyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-naphthalen-1-ylpiperazine-1- carboxamide

150 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(N,N-dimethylglycyl)amino]pyridin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

151 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(morpholin-4-ylacetyl)amino]pyridin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

152 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(piperidin-1-ylacetyl)amino]pyridin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

153 ethyl {4-[({4-({[3,5- bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

154 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(pyrrolidin-1-ylacetyl)amino]pyridin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

155 N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- yl)piperazine-1-carboxamide

156 N-[3,5-bis(trifluoromethyl)phenyl]-4- {4-[({2-[(N,N-diethylglycyl)amino]pyridin-4- yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

157 1-ethylpiperidin-4-yl {4-[({4-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

158 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

159 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(2-oxo-1,3-oxazolidin-3-yl)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3- yl]piperazine-1-carboxamide

160 2-(diethylamino)ethyl {4-[({4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate

161 methyl {4-({[2-(4-{[(3- ehtylphenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]carbamate

162 2-pyrrolidin-1-ylethyl {4-[({4-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3- yl}oxy)methyl]pyrimidin-2-yl}carbamate

163 2-piperidin-1-ylethyl {4-[({4-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo-nyl)piperazin-1-yl]-1,2,5-thiadiazol-3- yl}oxy)methyl]pyrimidin-2-yl}carbamate

164 methyl [4-({[2-(4-{[(3- bromophenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin- 2-yl]carbamate

165 methyl {4-[({2-[4-({[3- (methyloxy)phenyl]amino}carbonyl)pipe-razin-1-yl]pyridin-3- yl}oxy)methyl]pyridin-2-yl}carbamate

166 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(methyloxy)phenyl]piperazine-1- carboxamide

167 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(1-methylethyl)phenyl]piperazine-1- carboxamide

168 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-{3-[(trifluoromethyl)oxy]phenyl}piperazine- 1-carboxamide

169 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

170 N-(3-ethylphenyl)-4-[3-({[2-({[(3-ethylphenyl)amino]carbonyl}amino)pyri- din-4-yl]methyl}oxy)pyridin-2-yl]piperazine-1-carboxamide

171 N-(3-ethylphenyl)-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

172 N-(3-ethylphenyl)-4-(4-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

173 N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

174 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

175 4-[3-({[2-(acetylamino)pyridin-4- yl]methyl}oxy)pyridin-2-yl]-N-(3-ethylphenyl)piperazine-1-carboxamide

176 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethyl-4-fluorophenyl)piperazine-1- carboxamide

177 2-[4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)piperazin-1- yl]-N-[3,5-bis(trifluoromethyl)phenyl]acetamide

178 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-phenylpiperazine-1-carboxamide

179 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-chloro-5-ethylphenyl)piperazine-1- carboxamide

180 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide

181 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-bromo-5-ethylphenyl)piperazine-1- carboxamide

182 2-(4-methylpiperazin-1-yl)ethyl [4-({[2- (4-{[(3-ethylphenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]carbamate

183 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-chlorophenyl)piperazine-1-carboxamide

184 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-bromophenyl)piperazine-1-carboxamide

185 N-[4-({[2-(4-acetylpiperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2-yl]-2-(4-methylpiperazin-1-yl)acetamide

186 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-fluorophenyl)piperazine-1-carboxamide

187 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(4-fluorophenyl)piperazine-1-carboxamide

188 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(2-fluorophenyl)piperazine-1-carboxamide

189 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3,5-diethylphenyl)piperazine-1-carboxamide

190 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-5-bromopyridin-2-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

191 N-methyl-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

192 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

193 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(5-chloro-2-fluorophenyl)piperazine-1- carboxamide

194 4-(3-{[(2-amino-5-bromopyrimidin-4-yl)methyl]oxy}-5-bromopyridin-2-yl)- N-(3-ethylphenyl)piperazine-1-carboxamide

195 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2-fluoro-3- (trifluoromethyl)phenyl]piperazine-1- carboxamide

196 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

197 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3,5-dichlorophenyl)piperazine-1- carboxamide

198 N-(3-chloro-5-ethylphenyl)-4-(3-{[(2- {[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

199 N-(5-ethyl-2-fluorophenyl)-4-(3-{[(2- {[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

200 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-ethyl-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

201 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(3-ethylphenyl)piperazine-1-carboxamide

202 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(3-chloro-5-ethylphenyl)piperazine-1- carboxamide

203 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide

204 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-methylpiperazine-1-carboxamide

205 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-ethylpiperazine-1-carboxamide

206 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-cyclohexylpiperazine-1-carboxamide

207 4-({[2-(4-acetylpiperazin-1-yl)pyridin-3-yl]oxy}methyl)pyrimidin-2-amine

208 4-({[2-(4-propanoylpiperazin-1-yl)pyridin-3-yl]oxy}methyl)pyrimidin- 2-amine

209 N-(3-cyclopropylphenyl)-4-(3-{[(2- {[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

210 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-cyclopropylphenyl)piperazine-1- carboxamide

211 N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

212 N-[3-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

213 N-(3,5-dichlorophenyl)-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

214 4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- (trifluoromethyl)phenyl]piperazine-1-carboxamide

215 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(3,5-diethylphenyl)piperazine-1-carboxamide

216 4-(3-{[1-(2-aminopyrimidin-4- yl)ethyl]oxy}pyridin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

217 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(3,5-dichlorophenyl)piperazine-1- carboxamide

218 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-[3-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

219 4-[({2-[4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperazin-1-yl]pyridin-3- yl}oxy)methyl]pyrimidin-2-amine

220 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(2-methylpropyl)piperazine-1-carboxamide

221 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-chloro-5-ethylphenyl)piperazine-1- carboxamide

222 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide

223 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3,5-dichlorophenyl)piperazine-1- carboxamide

224 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-phenylpiperazine-1-carboxamide

225 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-[2-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

226 N-(3,5-diethylphenyl)-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)oxy]methyl}pyridin-2-yl)piperazine-1-carboxamide

227 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-methylpyridin-2-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

228 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-methylpyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

229 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

230 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-phenylpiperazine-1-carboxamide

231 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3- (trifluoromethyl)phenyl]piperazine-1- carboxamide

232 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[2-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

233 N-[3-chloro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

234 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-[3-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

235 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

236 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(3-bromo-5-ethylphenyl)piperazine-1- carboxamide

237 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

238 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-bromo-5-ethylphenyl)piperazine- 1-carboxamide

239 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

240 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

241 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-(3-ethyl-4-fluorophenyl)piperazine-1- carboxamide

242 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3,5-diethylphenyl)piperazine-1- carboxamide

243 N-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

244 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

245 4-(3-{[1-(2-aminopyrimidin-4- yl)ethyl]oxy}pyridin-2-yl)-N-(3-ethylphenyl)piperazine-1-carboxamide

246 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)-N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide

247 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethyl-5-fluorophenyl)piperazine-1- carboxamide

248 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]piperazine-1-carboxamide

249 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

250 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]-N- methylpiperazine-1-carboxamide

251 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyrazin-2-yl)-N-[3-(1-methylethyl)phenyl]piperazine-1- carboxamide

252 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-ethyl-4-fluorophenyl)piperazine-1- carboxamide

253 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-chloro-4-fluorophenyl)piperazine- 1-carboxamide

254 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[2,5- bis(methyloxy)phenyl]piperazine-1- carboxamide

255 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

256 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-(3-ethylphenyl)piperazine-1-carboxamide

257 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(5-chloro-2-fluorophenyl)piperazine- 1-carboxamide

258 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-{3- [(trifluoromethyl)oxy]phenyl}piperazine- 1-carboxamide

259 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-(methyloxy)phenyl]piperazine-1- carboxamide

260 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-ethyl-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

261 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-(1-methylethyl)phenyl]piperazine- 1-carboxamide

262 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[2-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

263 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3-fluorophenyl)piperazine-1- carboxamide

264 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[2-(ethyloxy)phenyl]piperazine-1- carboxamide

265 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-(3,4-difluorophenyl)piperazine-1- carboxamide

266 4-(4-{[(2-aminopyrimidin-4- yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3-(methylthio)phenyl]piperazine-1- carboxamide

267 N-(3-acetylphenyl)-4-(4-{[(2- aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1- carboxamide

268 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

269 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-(3-fluorophenyl)piperazine-1-carboxamide

270 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-phenylpiperazine-1-carboxamide

271 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-(3,5-dichlorophenyl)piperazine-1- carboxamide

272 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-[3-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

273 4-[4-({[6,7-bis(methyloxy)quinolin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]- N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

274 4-({[4-(4-{[3,5- bis(trifluoromethyl)phenyl]acetyl}pipera-zin-1-yl)-1,2,5-thiadiazol-3- yl]oxy}methyl)pyrimidin-2-amine

275 5-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbo- nyl)piperazin-1-yl]pyrazine-2-carboxamide

276 4-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,2,5-thiadiazol-3-yl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

277 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-[3-ethyl-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

278 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-(5-ethyl-2-fluorophenyl)piperazine-1-carboxamide

279 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-(3,5-diethylphenyl)piperazine-1-carboxamide

280 4-[({4-[4-(naphthalen-2- ylacetyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyrimidin- 2-amine

281 4-(2-{[(2-aminopyrimidin-4- yl)methyl]oxy}phenyl)-N-(3-chloro-5-ethylphenyl)piperazine-1-carboxamide

Another aspect of the invention is a pharmaceutical compositioncomprising the compound according to any one of embodiments[0021]-[0062] and a pharmaceutically acceptable carrier, hereinafterembodiment [0063].

Another aspect of the invention is a metabolite of the compound or thepharmaceutical composition according to any one of embodiments[0021]-[0063], hereinafter embodiment [0064].

Another aspect of the invention is a method of modulating the in vivoactivity of a kinase, the method comprising administering to a subjectan effective amount of a composition comprising at least one of thecompound according to any of embodiments [0021]-[0062] and thepharmaceutical composition according to embodiment [0063], hereinafterembodiment [0065].

Another aspect of the invention is the method according to embodiment[0065], wherein the kinase is Tie-2, hereinafter embodiment [0066].

Another aspect of the invention is the method according to embodiment[0066], wherein modulating the in vivo activity of Tie-2 comprisesinhibition of Tie-2.

Another aspect of the invention is a method of treating diseases ordisorders associated with uncontrolled, abnormal, and/or unwantedcellular activities, the method comprising administering, to a mammal inneed thereof, a therapeutically effective amount of a compositioncomprising at least one of the compound according to any of embodiments[0021]-[0062] and the pharmaceutical composition according to embodiment[0063].

Another aspect of the invention is a method of screening for modulatorof a Tie-2 kinase, the method comprising combining either a compositioncomprising at least one of the compound according to any of embodiments[0021]-[0062] and the pharmaceutical composition according to embodiment[0063], and at least one candidate agent and determining the effect ofthe candidate agent on the activity of said kinase.

Another aspect of the invention is a method of inhibiting proliferativeactivity in a cell, the method comprising administering an effectiveamount of at least one of the compound according to any of embodiments[0021]-[0062] and the pharmaceutical composition according to embodiment[0063].

DEFINITIONS

As used in the present specification, the following words and phrasesare generally intended to have the meanings as set forth below, exceptto the extent that the context in which they are used indicatesotherwise or they are expressly defined to mean something different.

The symbol “—” means a single bond, “═” means a double bond, “≡” means atriple bond. The symbol

 refers to a group on a double-bond as occupying either position on theterminus of a double bond to which the symbol is attached; that is, thegeometry, E- or Z—, of the double bond is ambiguous. When a group isdepicted removed from its parent formula, the

 symbol will be used at the end of the bond which was theoreticallycleaved in order to separate the group from its parent structuralformula.

Chemical formulae use descriptors such as “R¹” accompanied by a list offormulae or verbiage describing the scope of what is meant by thedescriptor. A subsequent descriptor such as “R^(1a)” is used to describesome subset of the scope of R¹, and “R^(1b)” is used to describe anothersubset of the scope of R¹, and so on. In such subsequent cases, allother formulae containing simply “R¹” are meant to include the entirescope of the descriptor.

When chemical structures are depicted or described, unless explicitlystated otherwise, all carbons are assumed to have hydrogen substitutionto conform to a valence of four. For example, in the structure on theleft-hand side of the schematic below there are nine hydrogens implied.The nine hydrogens are depicted in the right-hand structure. Sometimes aparticular atom in a structure is described in textual formula as havinga hydrogen or hydrogens as substitution (expressly defined hydrogen),for example, —CH₂CH₂—. It is understood by one of ordinary skill in theart that the aforementioned descriptive techniques are common in thechemical arts to provide brevity and simplicity to description ofotherwise complex structures.

In this application, some ring structures are depicted generically andwill be described textually. For example, in the schematic below, if inthe structure on the left, ring A is used to describe a “spirocyclyl,”then if ring A is cyclopropyl, there are at most four hydrogens on ringA (when “R” can also be —H). In another example, as depicted on theright side of the schematic below, if ring B is used to describe a“phenylene” then there can be at most four hydrogens on ring B (assumingdepicted cleaved bonds are not C—H bonds).

If a group “R” is depicted as “floating” on a ring system, as forexample in the formula:

then, unless otherwise defined, a substituent “R” may reside on any atomof the ring system, assuming replacement of a depicted, implied, orexpressly defined hydrogen from one of the ring atoms, so long as astable structure is formed.

If a group “R” is depicted as floating on a fused ring system, as forexample in the formulae:

then, unless otherwise defined, a substituent “R” may reside on any atomof the fused ring system, assuming replacement of a depicted hydrogen(for example the —NH— in the formula above), implied hydrogen (forexample as in the formula above, where the hydrogens are not shown butunderstood to be present), or expressly defined hydrogen (for examplewhere in the formula above, “X” equals ═CH—) from one of the ring atoms,so long as a stable structure is formed. In the example depicted, the“R” group may reside on either the 5-membered or the 6-membered ring ofthe fused ring system. In the formula depicted above, when y is 2 forexample, then the two “R's” may reside on any two atoms of the ringsystem, again assuming each replaces a depicted, implied, or expresslydefined hydrogen on the ring.

When a group “R” is depicted as existing on a ring system containingsaturated carbons, as for example in the formula:

where, in this example, “y” can be more than one, assuming each replacesa currently depicted, implied, or expressly defined hydrogen on thering; then, unless otherwise defined, where the resulting structure isstable, two “R's” may reside on the same carbon. A simple example iswhen R is a methyl group; there can exist a geminal dimethyl on a carbonof the depicted ring (an “annular” carbon). In another example, two R'son the same carbon, including that carbon, may form a ring, thuscreating a spirocyclic ring (a “spirocyclyl” group) structure with thedepicted ring as for example in the formula:

“Alkyl” is intended to include linear, branched, or cyclic hydrocarbonstructures and combinations thereof, inclusively. For example, “C₈alkyl” may refer to an n-octyl, iso-octyl, cyclohexylethyl, and thelike. Lower alkyl refers to alkyl groups of from one to six carbonatoms. Examples of lower alkyl groups include methyl, ethyl, propyl,isopropyl, butyl, s-butyl, t-butyl, isobutyl, pentyl, hexyl and thelike. Higher alkyl refers to alkyl groups containing more that eightcarbon atoms. Exemplary alkyl groups are those of C₂₀ or below.Cycloalkyl is a subset of alkyl and includes cyclic hydrocarbon groupsof from three to thirteen carbon atoms. Examples of cycloalkyl groupsinclude c-propyl, c-butyl, c-pentyl, norbornyl, adamantyl and the like.In this application, alkyl refers to alkanyl, alkenyl, and alkynylresidues (and combinations thereof); it is intended to includecyclohexylmethyl, vinyl, allyl, isoprenyl, and the like. Thus, when analkyl residue having a specific number of carbons is named, allgeometric isomers having that number of carbons are intended to beencompassed; thus, for example, either “butyl” or “C₄alkyl” is meant toinclude n-butyl, sec-butyl, isobutyl, t-butyl, isobutenyl and but-2-yneradicals; and for example, “propyl” or “C₃alkyl” each include n-propyl,propenyl, and isopropyl. Otherwise, if alkenyl and/or alkynyldescriptors are used in a particular definition of a group, for example“C₄alkyl” along “C₄alkenyl,” then C₄alkenyl geometric isomers are notmeant to be included in “C₄alkyl,” but other 4-carbon isomers are, forexample C₄alkynyl. For example, a more general description, intending toencompass the invention as a whole may describe a particular group as“C₁₋₈alkyl” while a preferred species may describe the same group asincluding, “C₁₋₈alkyl,” “C₁₋₆alkenyl” and “C₁₋₅alkynyl.”

“Alkylene” refers to straight or branched chain divalent radicalconsisting solely of carbon and hydrogen atoms, containing nounsaturation and having from one to ten carbon atoms, for example,methylene, ethylene, propylene, n-butylene and the like. Alkylene is asubset of alkyl, referring to the same residues as alkyl, but having twopoints of attachment and, specifically, fully saturated. Examples ofalkylene include ethylene (—CH₂CH₂—), propylene (—CH₂CH₂CH₂—),dimethylpropylene (—CH₂C(CH₃)₂CH₂—), and cyclohexylpropylene(—CH₂CH₂CH(C₆H₁₃)).

“Alkylidene” refers to a straight or branched chain unsaturated divalentradical consisting solely of carbon and hydrogen atoms, having from twoto ten carbon atoms, for example, ethylidene, propylidene, n-butylidene,and the like. Alkylidene is a subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment and,specifically, double bond unsaturation. The unsaturation presentincludes at least one double bond.

“Alkylidyne” refers to a straight or branched chain unsaturated divalentradical consisting solely of carbon and hydrogen atoms having from twoto ten carbon atoms, for example, propylid-2-ynyl, n-butylid-1-ynyl, andthe like. Alkylidyne is a subset of alkyl, referring to the sameresidues as alkyl, but having two points of attachment and,specifically, triple bond unsaturation. The unsaturation presentincludes at least one triple bond.

Any of the above radicals, “alkylene,” “alkylidene” and “alkylidyne,”when optionally substituted, may contain alkyl substitution which itselfcontains unsaturation. For example,2-(2-phenylethynyl-but-3-enyl)-naphthalene (IUPAC name) contains ann-butylid-3-ynyl radical with a vinyl substituent at the 2-position ofsaid radical.

“Alkoxy” or “alkoxyl” refers to the group —O-alkyl, for exampleincluding from one to eight carbon atoms of a straight, branched, cyclicconfiguration, unsaturated chains, and combinations thereof attached tothe parent structure through an oxygen atom. Examples include methoxy,ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy and the like.Lower-alkoxy refers to groups containing one to six carbons.

“Substituted alkoxy” refers to the group —O-(substituted alkyl), thesubstitution on the alkyl group generally containing more than onlycarbon (as defined by alkoxy). One exemplary substituted alkoxy group is“polyalkoxy” or —O-optionally substituted alkylene-optionallysubstituted alkoxy, and includes groups such as —OCH₂CH₂OCH₃, and glycolethers such as polyethyleneglycol and —O(CH₂CH₂O)_(x)CH₃, where x is aninteger of between about two and about twenty, in another example,between about two and about ten, and in a further example between abouttwo and about five. Another exemplary substituted alkoxy group ishydroxyalkoxy or —OCH₂(CH₂)_(y)OH, where y is for example an integer ofbetween about one and about ten, in another example y is an integer ofbetween about one and about four.

“Acyl” refers to groups of from one to ten carbon atoms of a straight,branched, cyclic configuration, saturated, unsaturated and aromatic andcombinations thereof, attached to the parent structure through acarbonyl functionality. One or more carbons in the acyl residue may bereplaced by nitrogen, oxygen or sulfur as long as the point ofattachment to the parent remains at the carbonyl. Examples includeacetyl, benzoyl, propionyl, isobutyryl, t-butoxycarbonyl,benzyloxycarbonyl and the like. Lower-acyl refers to groups containingone to six carbons.

“α-Amino Acids” refer to naturally occurring and commercially availableamino acids and optical isomers thereof. Typical natural andcommercially available α-amino acids are glycine, alanine, serine,homoserine, threonine, valine, norvaline, leucine, isoleucine,norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine,arginine, cysteine, homocysteine, methionine, phenylalanine,homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine,para-tyrosine, tryptophan, glutamine, asparagine, proline andhydroxyproline. A “side chain of an α-amino acid” refers to the radicalfound on the α-carbon of an α-amino acid as defined above, for example,hydrogen (for glycine), methyl (for alanine), benzyl (forphenylalanine), and the like.

“Amino” refers to the group —NH₂. “Substituted amino,” refers to thegroup —N(H)R or —N(R)R where each R is independently selected from thegroup: optionally substituted alkyl, optionally substituted alkoxy,optionally substituted aryl, optionally substituted heterocyclyl, acyl,carboxy, alkoxycarbonyl, sulfanyl, sulfinyl and sulfonyl, for example,diethylamino, methylsulfonylamino, and furanyl-oxy-sulfonamino.

“Aryl” refers to aromatic six- to fourteen-membered carbocyclic ring,for example, benzene, naphthalene, indane, tetralin, fluorene and thelike, univalent radicals. As univalent radicals, the aforementioned ringexamples are named, phenyl, naphthyl, indanyl, tetralinyl, andfluorenyl.

“Arylene” generically refers to any aryl that has at least two groupsattached thereto. For a more specific example, “phenylene” refers to adivalent phenyl ring radical. A phenylene, thus may have more than twogroups attached, but is defined by a minimum of two non-hydrogen groupsattached thereto.

“Arylalkyl” refers to a residue in which an aryl moiety is attached to aparent structure via one of an alkylene, alkylidene, or alkylidyneradical. Examples include benzyl, phenethyl, phenylvinyl, phenylallyland the like. Both the aryl, and the corresponding alkylene, alkylidene,or alkylidyne radical portion of an arylalkyl group may be optionallysubstituted. “Lower arylalkyl” refers to an arylalkyl where the “alkyl”portion of the group has one to six carbons; this can also be referredto as C₁₋₆ arylalkyl.

“Exo-alkenyl” refers to a double bond that emanates from an annularcarbon, and is not within the ring system, for example the double bonddepicted in the formula below.

In some examples, as appreciated by one of ordinary skill in the art,two adjacent groups on an aromatic system may be fused together to forma ring structure. The fused ring structure may contain heteroatoms andmay be optionally substituted with one or more groups. It shouldadditionally be noted that saturated carbons of such fused groups (i.e.saturated ring structures) can contain two substitution groups.

“Fused-polycyclic” or “fused ring system” refers to a polycyclic ringsystem that contains bridged or fused rings; that is, where two ringshave more than one shared atom in their ring structures. In thisapplication, fused-polycyclics and fused ring systems are notnecessarily all aromatic ring systems. Typically, but not necessarily,fused-polycyclics share a vicinal set of atoms, for example naphthaleneor 1,2,3,4-tetrahydro-naphthalene. A spiro ring system is not afused-polycyclic by this definition, but fused polycyclic ring systemsof the invention may themselves have spiro rings attached thereto via asingle ring atom of the fused-polycyclic.

“Halogen” or “halo” refers to fluorine, chlorine, bromine or iodine.“Haloalkyl” and “haloaryl” refer generically to alkyl and aryl radicalsthat are substituted with one or more halogens, respectively. Thus,“dihaloaryl,” “dihaloalkyl,” “trihaloaryl” etc. refer to aryl and alkylsubstituted with a plurality of halogens, but not necessarily aplurality of the same halogen; thus 4-chloro-3-fluorophenyl is withinthe scope of dihaloaryl.

“Heteroarylene” generically refers to any heteroaryl that has at leasttwo groups attached thereto. For a more specific example, “pyridylene”refers to a divalent pyridyl ring radical. A pyridylene, thus may havemore than two groups attached, but is defined by a minimum of twonon-hydrogen groups attached thereto.

“Heteroatom” refers to O, S, N, or P.

“Heterocyclyl” refers to a stable three- to fifteen-membered ringradical that consists of carbon atoms and from one to five heteroatomsselected from the group consisting of nitrogen, phosphorus, oxygen andsulfur. For purposes of this invention, the heterocyclyl radical may bea monocyclic, bicyclic or tricyclic ring system, which may include fusedor bridged ring systems as well as spirocyclic systems; and thenitrogen, phosphorus, carbon or sulfur atoms in the heterocyclyl radicalmay be optionally oxidized to various oxidation states. In a specificexample, the group —S(O)₀₋₂—, refers to —S— (sulfide), —S(O)—(sulfoxide), and —SO₂— (sulfone). For convenience, nitrogens,particularly but not exclusively, those defined as annular aromaticnitrogens, are meant to include their corresponding N-oxide form,although not explicitly defined as such in a particular example. Thus,for a compound of the invention having, for example, a pyridyl ring; thecorresponding pyridyl-N-oxide is meant to be included as anothercompound of the invention. In addition, annular nitrogen atoms may beoptionally quaternized; and the ring radical may be partially or fullysaturated or aromatic. Examples of heterocyclyl radicals include, butare not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl,benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl,naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl,phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl,quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl,tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl,4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl,imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl,pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl,oxazolidinyl, triazolyl, isoxazolyl, isoxazolidinyl, morpholinyl,thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl,isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl,octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl,decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl,benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl,thienyl, benzothieliyl, thiamorpholinyl, thiamorpholinyl sulfoxide,thiamorpholinyl sulfone, dioxaphospholanyl, and oxadiazolyl.

“Heteroalicyclic” refers specifically to a non-aromatic heterocyclylradical. A heteroalicyclic may contain unsaturation, but is notaromatic.

“Heteroaryl” refers specifically to an aromatic heterocyclyl radical.

“Heterocyclylalkyl” refers to a residue in which a heterocyclyl isattached to a parent structure via one of an alkylene, alkylidene, oralkylidyne radical. Examples include (4-methylpiperazin-1-yl)methyl,(morpholin-4-yl)methyl, (pyridine-4-yl)methyl, 2-(oxazolin-2-yl)ethyl,4-(4-methylpiperazin-1-yl)-2-butenyl, and the like. Both theheterocyclyl, and the corresponding alkylene, alkylidene, or alkylidyneradical portion of a heterocyclylalkyl group may be optionallysubstituted. “Lower heterocyclylalkyl” refers to a heterocyclylalkylwhere the “alkyl” portion of the group has one to six carbons.“Heteroalicyclylalkyl” refers specifically to a heterocyclylalkyl wherethe heterocyclyl portion of the group is non-aromatic; and“heteroarylalkyl” refers specifically to a heterocyclylalkyl where theheterocyclyl portion of the group is aromatic Such terms may bedescribed in more than one way, for example, “lower heterocyclylalkyl”and “heterocyclyl C₁₋₆alkyl” are equivalent terms.

“Optional” or “optionally” means that the subsequently described eventor circumstance may or may not occur, and that the description includesinstances where said event or circumstance occurs and instances in whichit does not. One of ordinary skill in the art would understand that,with respect to any molecule described as containing one or moreoptional substituents, that only sterically practical and/orsynthetically feasible compounds are meant to be included. “Optionallysubstituted” refers to all subsequent modifiers in a term, for examplein the term “optionally substituted arylC₁₋₈alkyl,” optionalsubstitution may occur on both the “C₁₋₈alkyl” portion and the “aryl”portion of the molecule; and for example, optionally substituted alkylincludes optionally substituted cycloalkyl groups, which in turn aredefined as including optionally substituted alkyl groups, potentially adinfinitum. A list of exemplary optional substitutions is included belowin the definition of “substituted.”

“Saturated bridged ring system” refers to a bicyclic or polycyclic ringsystem that is not aromatic. Such a system may contain isolated orconjugated unsaturation, but not aromatic or heteroaromatic rings in itscore structure (but may have aromatic substitution thereon). Forexample, hexahydro-furo[3,2-b]furan, 2,3,3a,4,7,7a-hexahydro-1H-indene,7-aza-bicyclo[2.2.1]heptane, and 1,2,3,4,4a,5,8,8a-octahydro-naphthaleneare all included in the class “saturated bridged ring system.

“Spirocyclyl” or “spirocyclic ring” refers to a ring originating from aparticular annular carbon of another ring. For example, as depictedbelow, a ring atom of a saturated bridged ring system (rings B and B′),but not a bridgehead atom, can be a shared atom between the saturatedbridged ring system and a spirocyclyl (ring A) attached thereto. Aspirocyclyl can be carbocyclic or heteroalicyclic.

“Substituted” alkyl, aryl, and heterocyclyl, refer respectively toalkyl, aryl, and heterocyclyl, wherein one or more (for example up toabout five, in another example, up to about three) hydrogen atoms arereplaced by a substituent independently selected from: optionallysubstituted alkyl (for example, fluoromethyl, hydroxypropyl,nitromethyl, aminoethyl and the like.), optionally substituted aryl (forexample, 4-hydroxyphenyl, 2,3-difluorophenyl, and the like), optionallysubstituted arylalkyl (for example, 1-phenyl-ethyl,para-methoxyphenylethyl and the like), optionally substitutedheterocyclylalkyl (for example, 1-pyridin-3-yl-ethyl, N-ethylmorphonlinoand the like), optionally substituted heterocyclyl (for example,5-chloro-pyridin-3-yl, 1-methyl-piperidin-4-yl and the like), optionallysubstituted alkoxy (for example methoxyethoxy, hydroxypropyloxy,methylenedioxy and the like), optionally substituted amino (for example,methylamino, diethylamino, trifluoroacetylamino and the like),optionally substituted amidino, optionally substituted aryloxy (forexample, phenoxy, para-chlorophenoxy, meta-aminophenoxy,para-phenoxyphenoxy and the like), optionally substituted arylalkyloxy(for example, benzyloxy, 3-chlorobenzyloxy, meta-phenoxybenzyloxy andthe like), carboxy (—CO₂H), optionally substituted carboalkoxy (that is,acyloxy or —OC(═O)R), optionally substituted carboxyalkyl (that is,esters or —CO₂R), optionally substituted carboxamido, optionallysubstituted benzyloxycarbonylamino (CBZ-amino), cyano, optionallysubstituted acyl, halogen, hydroxy, nitro, optionally substitutedalkylsulfanyl, optionally substituted alkylsulfinyl, optionallysubstituted alkylsulfonyl, thiol, oxo, carbamyl, optionally substitutedacylamino, optionally substituted hydrazino, optionally substitutedhydroxylamino, and optionally substituted sulfonamido.

“Sulfanyl” refers to the groups: —S-(optionally substituted alkyl),—S-(optionally substituted aryl), and —S-(optionally substitutedheterocyclyl).

“Sulfinyl” refers to the groups: —S(O)—H, —S(O)-(optionally substitutedalkyl), —S(O)-optionally substituted aryl), and —S(O)-(optionallysubstituted heterocyclyl).

“Sulfonyl” refers to the groups: —S(O₂)—H, —S(O₂)-(optionallysubstituted alkyl), —S(O₂)-optionally substituted aryl),—S(O₂)-(optionally substituted heterocyclyl), —S(O₂)-(optionallysubstituted alkoxy), —S(O₂)-optionally substituted aryloxy), and—S(O₂)-(optionally substituted heterocyclyloxy).

“Yield” for each of the reactions described herein is expressed as apercentage of the theoretical yield.

Some of the compounds of the invention may have imino, amino, oxo orhydroxy substituents off aromatic heterocyclyl systems. For purposes ofthis disclosure, it is understood that such imino, amino, oxo or hydroxysubstituents may exist in their corresponding tautomeric form, i.e.,amino, imino, hydroxy or oxo, respectively.

Compounds of the invention are named according to systematic applicationof the nomenclature rules agreed upon by the International Union of Pureand Applied Chemistry (IUPAC), International Union of Biochemistry andMolecular Biology (IUBMB), and the Chemical Abstracts Service (CAS).

The compounds of the invention, or their pharmaceutically acceptablesalts, may have asymmetric carbon atoms, oxidized sulfur atoms orquaternized nitrogen atoms in their structure.

The compounds of the invention and their pharmaceutically acceptablesalts may exist as single stereoisomers, racemates, and as mixtures ofenantiomers and diastereomers. The compounds may also exist as geometricisomers. All such single stereoisomers, racemates and mixtures thereof,and geometric isomers are intended to be within the scope of thisinvention.

It is assumed that when considering generic descriptions of compounds ofthe invention for the purpose of constructing a compound, suchconstruction results in the creation of a stable structure. That is, oneof ordinary skill in the art would recognize that there cantheoretically be some constructs which would not normally be consideredas stable compounds (that is, sterically practical and/or syntheticallyfeasible, supra).

When a particular group with its bonding structure is denoted as beingbonded to two partners; that is, a divalent radical, for example,—OCH₂—, then it is understood that either of the two partners may bebound to the particular group at one end, and the other partner isnecessarily bound to the other end of the particular group, unlessstated explicitly otherwise. Stated another way, divalent radicals arenot to be construed as limited to the depicted orientation, for example“—OCH₂—” is meant to mean not only “—OCH₂—” as drawn, but also “—CH₂O—.”

Methods for the preparation and/or separation and isolation of singlestereoisomers from racemic mixtures or non-racemic mixtures ofstereoisomers are well known in the art. For example, optically active(R)- and (S)-isomers may be prepared using chiral synthons or chiralreagents, or resolved using conventional techniques. Enantiomers (R- andS-isomers) may be resolved by methods known to one of ordinary skill inthe art, for example by: formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallization; viaformation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, selective reaction of one enantiomer withan enantiomer-specific reagent, for example enzymatic oxidation orreduction, followed by separation of the modified and unmodifiedenantiomers; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support, such as silica with abound chiral ligand or in the presence of a chiral solvent. It will beappreciated that where a desired enantiomer is converted into anotherchemical entity by one of the separation procedures described above, afurther step may be required to liberate the desired enantiomeric form.Alternatively, specific enantiomer may be synthesized by asymmetricsynthesis using optically active reagents, substrates, catalysts orsolvents, or by converting on enantiomer to the other by asymmetrictransformation. For a mixture of enantiomers, enriched in a particularenantiomer, the major component enantiomer may be further enriched (withconcomitant loss in yield) by recrystallization.

“Patient” for the purposes of the present invention includes humans andother animals, particularly mammals, and other organisms. Thus themethods are applicable to both human therapy and veterinaryapplications. In a preferred embodiment the patient is a mammal, and ina most preferred embodiment the patient is human.

“Kinase-dependent diseases or conditions” refer to pathologic conditionsthat depend on the activity of one or more protein kinases. Kinaseseither directly or indirectly participate in the signal transductionpathways of a variety of cellular activities including proliferation,adhesion, migration, differentiation and invasion. Diseases associatedwith kinase activities include tumor growth, the pathologicneovascularization that supports solid tumor growth, and associated withother diseases where excessive local vascularization is involved such asocular diseases (diabetic retinopathy, age-related macular degeneration,and the like) and inflammation (psoriasis, rheumatoid arthritis, and thelike).

While not wishing to be bound to theory, phosphatases can also play arole in “kinase-dependent diseases or conditions” as cognates ofkinases; that is, kinases phosphorylate and phosphatasesdephosphorylate, for example protein substrates. Therefore compounds ofthe invention, while modulating kinase activity as described herein, mayalso modulate, either directly or indirectly, phosphatase activity. Thisadditional modulation, if present, may be synergistic (or not) toactivity of compounds of the invention toward a related or otherwiseinterdependent kinase or kinase family. In any case, as statedpreviously, the compounds of the invention are useful for treatingdiseases characterized in part by abnormal levels of cell proliferation(i.e. tumor growth), programmed cell death (apoptosis), cell migrationand invasion and angiogenesis associated with tumor growth.

“Therapeutically effective amount” is an amount of a compound of theinvention, that when administered to a patient, ameliorates a symptom ofthe disease. The amount of a compound of the invention which constitutesa “therapeutically effective amount” will vary depending on thecompound, the disease state and its severity, the age of the patient tobe treated, and the like. The therapeutically effective amount can bedetermined routinely by one of ordinary skill in the art having regardto his own knowledge and to this disclosure.

“Cancer” refers to cellular-proliferative disease states, including butnot limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma,rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma andteratoma; Lung: bronchogenic carcinoma (squamous cell, undifferentiatedsmall cell, undifferentiated large cell, adenocarcinoma), alveolar(bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma,chondromatous hanlartoma, inesothelioma; Gastrointestinal: esophagus(squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma),stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductaladenocarcinoma, insulinorna, glucagonoma, gastrinoma, carcinoid tumors,vipoma), small bowel (adenocarcinorna, lymphoma, carcinoid tumors,Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma,fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma,hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma,Wilm's tumor [neplrroblastoma], lymphoma, leukemia), bladder and urethra(squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma),prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma,embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma,interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors,lipoma); liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma,hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma; Bone:osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibroushistiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma(reticulum cell sarcoma), multiple myeloma, malignant giant cell tumorchordoma, osteochronfroma (osteocartilaginous exostoses), benignchondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma andgiant cell tumors; Nervous system: skull (osteoma, hemangioma,granuloma, xanthoma, osteitis defornians), meninges (meningioma,meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma,glioma, ependymoma, germinoma [pinealoma], glioblastoma multiform,oligodendroglioma, schwannoma, retinoblastoma, congenital tumors),spinal cord neurofibroma, meningioma, glioma, sarcoma); Gynecological:uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumorcervical dysplasia), ovaries (ovarian carcinoma [serouscystadenocarcinoma, mucinous cystadenocarcinoma, unclassifiedcarcinoma], granulosa-thecal cell tumors, SertoliLeydig cell tumors,dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma,intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma),vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma(embryonal rhabdomyosarcoma], fallopian tubes (carcinoma); Hematologic:blood (myeloid leukemia [acute and chronic], acute lymphoblasticleukemia, chronic lymphocytic leukemia, myeloproliferative diseases,multiple myeloma, myelodysplastic syndrome), Hodgkin's disease,non-Hodgkin's lymphoma [malignant lymphoma]; Skin: malignant melanoma,basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, molesdysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;and Adrenal lands: neuroblastoma. Thus, the term “cancerous cell” asprovided herein, includes a cell afflicted by any one of theabove-identified conditions.

“Pharmaceutically acceptable acid addition salt” refers to those saltsthat retain the biological effectiveness of the free bases and that arenot biologically or otherwise undesirable, formed with inorganic acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like, as well as organic acids such as aceticacid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Exemplary salts are the ammonium, potassium, sodium, calcium,and magnesium salts. Salts derived from pharmaceutically acceptableorganic non-toxic bases include, but are not limited to, salts ofprimary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines and basic ionexchange resins, such as isopropylamine, trimethylamine, diethylamine,triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine,glucosamine, methylglucamine, theobromine, purines, piperazine,piperidine, N-ethylpiperidine, polyamine resins, and the like. Exemplaryorganic bases are isopropylamine, diethylamine, ethanolamine,trimethylamine, dicyclohexylamine, choline, and caffeine. (See, forexample, S. M. Berge, et al., “Pharmaceutical Salts,” J. Pharm. Sci.,1977; 66:1-19 which is incorporated herein by reference.)

“Prodrug” refers to compounds that are transformed (typically rapidly)in vivo to yield the parent compound of the above formulae, for example,by hydrolysis in blood. Common examples include, but are not limited to,ester and amide forms of a compound having an active form bearing acarboxylic acid moiety. Examples of pharmaceutically acceptable estersof the compounds of this invention include, but are not limited to,alkyl esters (for example with between about one and about six carbons)wherein the alkyl group is a straight or branched chain. Acceptableesters also include cycloalkyl esters and arylalkyl esters such as, butnot limited to benzyl. Examples of pharmaceutically acceptable amides ofthe compounds of this invention include, but are not limited to, primaryamides, and secondary and tertiary alkyl amides (for example withbetween about one and about six carbons). Amides and esters of thecompounds of the present invention may be prepared according toconventional methods. A thorough discussion of prodrugs is provided inT. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987, both of which are incorporated herein by referencefor all purposes.

“Metabolite” refers to the break-down or end product of a compound orits salt produced by metabolism or biotransformation in the animal orhuman body; for example, biotransformation to a more polar molecule suchas by oxidation, reduction, or hydrolysis, or to a conjugate (seeGoodman and Gilman, “The Pharmacological Basis of Therapeutics” 8.sup.thEd., Pergamon Press, Gilman et al. (eds), 1990 for a discussion ofbiotransformation). As used herein, the metabolite of a compound of theinvention or its salt may be the biologically active form of thecompound in the body. In one example, a prodrug may be used such thatthe biologically active form, a metabolite, is released in vivo. Inanother example, a biologically active metabolite is discoveredserendipitously, that is, no prodrug design per se was undertaken. Anassay for activity of a metabolite of a compound of the presentinvention is known to one of skill in the art in light of the presentdisclosure.

In addition, the compounds of the present invention can exist inunsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms for the purposesof the present invention.

In addition, it is intended that the present invention cover compoundsmade either using standard organic synthetic techniques, includingcombinatorial chemistry or by biological methods, such as bacterialdigestion, metabolism, enzymatic conversion, and the like.

“Treating” or “treatment” as used herein covers the treatment of adisease-state in a human, which disease-state is characterized byabnormal cellular proliferation, and invasion and includes at least oneof: (i) preventing the disease-state from occurring in a human, inparticular, when such human is predisposed to the disease-state but hasnot yet been diagnosed as having it; (ii) inhibiting the disease-state,i.e., arresting its development; and (iii) relieving the disease-state,i.e., causing regression of the disease-state. As is known in the art,adjustments for systemic versus localized delivery, age, body weight,general health, sex, diet, time of administration, drug interaction andthe severity of the condition may be necessary, and will beascertainable with routine experimentation by one of ordinary skill inthe art.

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particular c-Met, c-Kit, KDR,flt-3, or flt-4-ligand complexes, and their corresponding x-raystructure coordinates can be used to reveal new structural informationuseful for understanding the biological activity of kinases as describedherein. As well, the key structural features of the aforementionedproteins, particularly, the shape of the ligand binding site, are usefulin methods for designing or identifying selective modulators of kinasesand in solving the structures of other proteins with similar features.Such protein-ligand complexes, having compounds of the invention astheir ligand component, are an aspect of the invention.

As well, one of ordinary skill in the art would appreciate that suchsuitable x-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of kinases. Such methods may be characterized by the followingaspects: a) introducing into a suitable computer program, informationdefining a ligand binding domain of a kinase in a conformation (e.g. asdefined by x-ray structure coordinates obtained from suitable x-rayquality crystals as described above) wherein the computer programcreates a model of the three dimensional structures of the ligandbinding domain, b) introducing a model of the three dimensionalstructure of a candidate agent in the computer program, c) superimposingthe model of the candidate agent on the model of the ligand bindingdomain, and d) assessing whether the candidate agent model fitsspatially into the ligand binding domain. Aspects a-d are notnecessarily carried out in the aforementioned order. Such methods mayfurther entail: performing rational drug design with the model of thethree-dimensional structure, and selecting a potential candidate agentin conjunction with computer modeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor kinase modulation, and determining whether said candidate agentmodulates kinase activity in the assay. Such methods may also includeadministering the candidate agent, determined to modulate kinaseactivity, to a mammal suffering from a condition treatable by kinasemodulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a kinase. Such a method may be characterized bythe following aspects: a) creating a computer model of a kinase bindingpocket using structure coordinates obtained from suitable x-ray qualitycrystals of the kinase, b) employing computational algorithms to performa fitting operation between the test agent and the computer model of thebinding pocket, and c) analyzing the results of the fitting operation toquantify the association between the test agent and the computer modelof the binding pocket.

General Administration

Administration of the compounds of the invention, or theirpharmaceutically acceptable salts, in pure form or in an appropriatepharmaceutical composition, can be carried out via any of the acceptedmodes of administration or agents for serving similar utilities. Thus,administration can be, for example, orally, nasally, parenterally(intravenous, intramuscular, or subcutaneous), topically, transdermally,intravaginally, intravesically, intracistemally, or rectally, in theform of solid, semi-solid, lyophilized powder, or liquid dosage forms,such as for example, tablets, suppositories, pills, soft elastic andhard gelatin capsules, powders, solutions, suspensions, or aerosols, orthe like, preferably in unit dosage forms suitable for simpleadministration of precise dosages.

The compositions will include a conventional pharmaceutical carrier orexcipient and a compound of the invention as the/an active agent, and,in addition, may include other medicinal agents, pharmaceutical agents,carriers, adjuvants, etc. Compositions of the invention may be used incombination with anticancer or other agents that are generallyadministered to a patient being treated for cancer. Adjuvants includepreserving, wetting, suspending, sweetening, flavoring, perfuming,emulsifying, and dispensing agents. Prevention of the action ofmicroorganisms can be ensured by various antibacterial and antifungalagents, for example, parabens, chlorobutanol, phenol, sorbic acid, andthe like. It may also be desirable to include isotonic agents, forexample sugars, sodium chloride, and the like. Prolonged absorption ofthe injectable pharmaceutical form can be brought about by the use ofagents delaying absorption, for example, aluminum monostearate andgelatin.

If desired, a pharmaceutical composition of the invention may alsocontain minor amounts of auxiliary substances such as wetting oremulsifying agents, pH buffering agents, antioxidants, and the like,such as, for example, citric acid, sorbitan monolaurate, triethanolamineoleate, butylated hydroxytoluene, etc.

Compositions suitable for parenteral injection may comprisephysiologically acceptable sterile aqueous or nonaqueous solutions,dispersions, suspensions or emulsions, and sterile powders forreconstitution into sterile injectable solutions or dispersions.Examples of suitable aqueous and nonaqueous carriers, diluents, solventsor vehicles include water, ethanol, polyols (propyleneglycol,polyethyleneglycol, glycerol, and the like), suitable mixtures thereof,vegetable oils (such as olive oil) and injectable organic esters such asethyl oleate. Proper fluidity can be maintained, for example, by the useof a coating such as lecithin, by the maintenance of the requiredparticle size in the case of dispersions and by the use of surfactants.

One preferable route of administration is oral, using a convenient dailydosage regimen that can be adjusted according to the degree of severityof the disease-state to be treated.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms, the activecompound is admixed with at least one inert customary excipient (orcarrier) such as sodium citrate or dicalcium phosphate or (a) fillers orextenders, as for example, starches, lactose, sucrose, glucose,mannitol, and silicic acid, (b) binders, as for example, cellulosederivatives, starch, alignates, gelatin, polyvinylpyrrolidone, sucrose,and gum acacia, (c) humectants, as for example, glycerol, (d)disintegrating agents, as for example, agar-agar, calcium carbonate,potato or tapioca starch, alginic acid, croscarmellose sodium, complexsilicates, and sodium carbonate, (e) solution retarders, as for exampleparaffin, (f) absorption accelerators, as for example, quaternaryammonium compounds, (g) wetting agents, as for example, cetyl alcohol,and glycerol monostearate, magnesium stearate and the like (h)adsorbents, as for example, kaolin and bentonite, and (i) lubricants, asfor example, talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In thecase of capsules, tablets, and pills, the dosage forms may also comprisebuffering agents.

Solid dosage forms as described above can be prepared with coatings andshells, such as enteric coatings and others well known in the art. Theymay contain pacifying agents, and can also be of such composition thatthey release the active compound or compounds in a certain part of theintestinal tract in a delayed manner. Examples of embedded compositionsthat can be used are polymeric substances and waxes. The activecompounds can also be in microencapsulated form, if appropriate, withone or more of the above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirs. Suchdosage forms are prepared, for example, by dissolving, dispersing, etc.,a compound(s) of the invention, or a pharmaceutically acceptable saltthereof, and optional pharmaceutical adjuvants in a carrier, such as,for example, water, saline, aqueous dextrose, glycerol, ethanol and thelike; solubilizing agents and emulsifiers, as for example, ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,dimethylformamide; oils, in particular, cottonseed oil, groundnut oil,corn germ oil, olive oil, castor oil and sesame oil, glycerol,tetrahydrofurfuryl alcohol, polyethyleneglycols and fatty acid esters ofsorbitan; or mixtures of these substances, and the like, to thereby forma solution or suspension.

Suspensions, in addition to the active compounds, may contain suspendingagents, as for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar and tragacanth, or mixtures of thesesubstances, and the like.

Compositions for rectal administrations are, for example, suppositoriesthat can be prepared by mixing the compounds of the present inventionwith for example suitable non-irritating excipients or carriers such ascocoa butter, polyethyleneglycol or a suppository wax, which are solidat ordinary temperatures but liquid at body temperature and therefore,melt while in a suitable body cavity and release the active componenttherein.

Dosage forms for topical administration of a compound of this inventioninclude ointments, powders, sprays, and inhalants. The active componentis admixed under sterile conditions with a physiologically acceptablecarrier and any preservatives, buffers, or propellants as may berequired. Ophthalmic formulations, eye ointments, powders, and solutionsare also contemplated as being within the scope of this invention.

Generally, depending on the intended mode of administration, thepharmaceutically acceptable compositions will contain about 1% to about99% by weight of a compound(s) of the invention, or a pharmaceuticallyacceptable salt thereof, and 99% to 1% by weight of a suitablepharmaceutical excipient. In one example, the composition will bebetween about 5% and about 75% by weight of a compound(s) of theinvention, or a pharmaceutically acceptable salt thereof, with the restbeing suitable pharmaceutical excipients.

Actual methods of preparing such dosage forms are known, or will beapparent, to those skilled in this art; for example, see Remington'sPharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton,Pa., 1990). The composition to be administered will, in any event,contain a therapeutically effective amount of a compound of theinvention, or a pharmaceutically acceptable salt thereof, for treatmentof a disease-state in accordance with the teachings of this invention.

The compounds of the invention, or their pharmaceutically acceptablesalts, are administered in a therapeutically effective amount which willvary depending upon a variety of factors including the activity of thespecific compound employed, the metabolic stability and length of actionof the compound, the age, body weight, general health, sex, diet, modeand time of administration, rate of excretion, drug combination, theseverity of the particular disease-states, and the host undergoingtherapy. The compounds of the present invention can be administered to apatient at dosage levels in the range of about 0.1 to about 1,000 mg perday. For a normal human adult having a body weight of about 70kilograms, a dosage in the range of about 0.01 to about 100 mg perkilogram of body weight per day is an example. The specific dosage used,however, can vary. For example, the dosage can depend on a number offactors including the requirements of the patient, the severity of thecondition being treated, and the pharmacological activity of thecompound being used. The determination of optimum dosages for aparticular patient is well known to one of ordinary skill in the art.

Utility of Compounds of the Invention as Screening Agents

To employ the compounds of the invention in a method of screening forcandidate agents that bind to, for example Tie-2 receptor kinase, theprotein is bound to a support, and a compound of the invention is addedto the assay. Alternatively, the compound of the invention is bound tothe support and the protein is added. Classes of candidate agents amongwhich novel binding agents may be sought include specific antibodies,non-natural binding agents identified in screens of chemical libraries,peptide analogs, etc. Of particular interest are screening assays forcandidate agents that have a low toxicity for human cells. A widevariety of assays may be used for this purpose, including labeled invitro protein-protein binding assays, electrophoretic mobility shiftassays, immunoassays for protein binding, functional assays(phosphorylation assays, etc.) and the like.

The determination of the binding of the candidate agent to, for example,Tie-2 protein may be done in a number of ways. In one example, thecandidate agent (the compound of the invention) is labeled, for example,with a fluorescent or radioactive moiety and binding determineddirectly. For example, thus may be done by attaching all or a portion ofthe Tie-2 protein to a solid support, adding a labeled agent (forexample a compound of the invention in which at least one atom has beenreplaced by a detectable isotope), washing off excess reagent, anddetermining whether the amount of the label is that present on the solidsupport. Various blocking and washing steps may be utilized as is knownin the art.

By “labeled” herein is meant that the compound is either directly orindirectly labeled with a label which provides a detectable signal, forexample, radioisotope, fluorescent tag, enzyme, antibodies, particlessuch as magnetic particles, chemiluminescent tag, or specific bindingmolecules, and the like. Specific binding molecules include pairs, suchas biotin and streptavidin, digoxin and antidigoxin, and the like. Forthe specific binding members, the complementary member would normally belabeled with a molecule which provides for detection, in accordance withknown procedures, as outlined above. The label can directly orindirectly provide a detectable signal.

In some embodiments, only one of the components is labeled. For example,Tie-2 protein may be labeled at tyrosine positions using ¹²⁵I, or withfluorophores. Alternatively, more than one component may be labeled withdifferent labels; using ¹²⁵I for the proteins, for example, and afluorophor for the candidate agents.

The compounds of the invention may also be used as competitors to screenfor additional drug candidates. “candidate bioactive agent” or “drugcandidate” or grammatical equivalents as used herein describe anymolecule, e.g., protein, oligopeptide, small organic molecule,polysaccharide, polynucleotide, etc., to be tested for bioactivity. Theymay be capable of directly or indirectly altering the cellularproliferation phenotype or the expression of a cellular proliferationsequence, including both nucleic acid sequences and protein sequences.In other cases, alteration of cellular proliferation protein bindingand/or activity is screened. In the case where protein binding oractivity is screened, some embodiments exclude molecules already knownto bind to that particular protein. Exemplary embodiments of assaysdescribed herein include candidate agents, which do not bind the targetprotein in its endogenous native state, termed herein as “exogenous”agents. In one example, exogenous agents further exclude antibodies toTie-2.

Candidate agents can encompass numerous chemical classes, thoughtypically they are organic molecules having a molecular weight of morethan about 100 and less than about 2,500 daltons. Candidate agentscomprise functional groups necessary for structural interaction withproteins, particularly hydrogen bonding and lipophilic binding, andtypically include at least an amine, carbonyl, hydroxyl, ether, orcarboxyl group, for example at least two of the functional chemicalgroups. The candidate agents often comprise cyclical carbon orheterocyclyl structures and/or aromatic or polyaromatic structuressubstituted with one or more of the above functional groups. Candidateagents are also found among biomolecules including peptides,saccharides, fatty acids, steroids, purines, pyrimidines, derivatives,structural analogs, or combinations thereof.

Candidate agents are obtained from a wide variety of sources includinglibraries of synthetic or natural compounds. For example, numerous meansare available for random and directed synthesis of a wide variety oforganic compounds and biomolecules, including expression of randomizedoligonucleotides. Alternatively, libraries of natural compounds in theform of bacterial, fungal, plant and animal extracts are available orreadily produced. Additionally, natural or synthetically producedlibraries and compounds are readily modified through conventionalchemical, physical and biochemical means. Known pharmacological agentsmay be subjected to directed or random chemical modifications, such asacylation, alkylation, esterification, amidification to producestructural analogs.

In one example, the binding of the candidate agent is determined throughthe use of competitive binding assays. In this example, the competitoris a binding moiety known to bind to Tie-2, such as an antibody,peptide, binding partner, ligand, etc. Under certain circumstances,there may be competitive binding as between the candidate agent and thebinding moiety, with the binding moiety displacing the candidate agent.

In some embodiments, the candidate agent is labeled. Either thecandidate agent, or the competitor, or both, is added first to Tie-2protein for a time sufficient to allow binding, if present. Incubationsmay be performed at any temperature that facilitates optimal activity,typically between 4° C. and 40° C.

Incubation periods are selected for optimum activity, but may also beoptimized to facilitate rapid high throughput screening. Typicallybetween 0.1 and 1 hour will be sufficient. Excess reagent is generallyremoved or washed away. The second component is then added, and thepresence or absence of the labeled component is followed, to indicatebinding.

In one example, the competitor is added first, followed by the candidateagent. Displacement of the competitor is an indication the candidateagent is binding to Tie-2 and thus is capable of binding to, andpotentially modulating, the activity of the Tie-2. In this embodiment,either component can be labeled. Thus, for example, if the competitor islabeled, the presence of label in the wash solution indicatesdisplacement by the agent. Alternatively, if the candidate agent islabeled, the presence of the label on the support indicatesdisplacement.

In an alternative embodiment, the candidate agent is added first, withincubation and washing, followed by the competitor. The absence ofbinding by the competitor may indicate the candidate agent is bound toTie-2 with a higher affinity. Thus, if the candidate agent is labeled,the presence of the label on the support, coupled with a lack ofcompetitor binding, may indicate the candidate agent is capable ofbinding to Tie-2.

It may be of value to identify the binding site of Tie-2. This can bedone in a variety of ways. In one embodiment, once Tie-2 has beenidentified as binding to the candidate agent, the Tie-2 is fragmented ormodified and the assays repeated to identify the necessary componentsfor binding.

Modulation is tested by screening for candidate agents capable ofmodulating the activity of Tie-2 comprising the steps of combining acandidate agent with Tie-2, as above, and determining an alteration inthe biological activity of the Tie-2. Thus, in this embodiment, thecandidate agent should both bind to (although this may not benecessary), and alter its biological or biochemical activity as definedherein. The methods include both in vitro screening methods and in vivoscreening of cells for alterations in cell viability, morphology, andthe like.

Alternatively, differential screening may be used to identify drugcandidates that bind to native Tie-2, but cannot bind to modified Tie-2.

Positive controls and negative controls can be used in the assays. Forexample, all control and test samples are performed in at leasttriplicate to obtain statistically significant results. Incubation ofsamples is for a time sufficient for the binding of the agent to theprotein. Following incubation, samples are washed free ofnon-specifically bound material and the amount of bound, generallylabeled agent determined. For example, where a radiolabel is employed,the samples can be counted in a scintillation counter to determine theamount of bound compound.

A variety of other reagents can be included in the screening assays.These include reagents like salts, neutral proteins, e.g., albumin,detergents, etc which may be used to facilitate optimal protein-proteinbinding and/or reduce non-specific or background interactions. Alsoreagents that otherwise improve the efficiency of the assay, such asprotease inhibitors, nuclease inhibitors, anti-microbial agents, etc.,may be used. The mixture of components can be added in any order thatprovides for the requisite binding.

One of ordinary skill in the art would understand that certaincrystallized, protein-ligand complexes, in particular Tie-2-ligandcomplexes, and their corresponding x-ray structure coordinates can beused to reveal new structural information useful for understanding thebiological activity of Tie-2 kinase's as described herein. As well, thekey structural features of the aforementioned proteins, particularly,the shape of the ligand binding site, are useful in methods fordesigning or identifying selective modulators of Tie-2 kinase's and insolving the structures of other proteins with similar features. Ligandsof such complexes may include compounds of the invention as describedherein.

As well, one of ordinary skill in the art would appreciate that suchsuitable x-ray quality crystals can be used as part of a method ofidentifying a candidate agent capable of binding to and modulating theactivity of Tie-2 kinases. Such methods may be characterized by thefollowing aspects: a) introducing into a suitable computer program,information defining a ligand binding domain of a Tie-2 kinase in aconformation (e.g. as defined by x-ray structure coordinates obtainedfrom suitable x-ray quality crystals as described above) wherein thecomputer program creates a model of the three dimensional structures ofthe ligand binding domain, b) introducing a model of the threedimensional structure of a candidate agent in the computer program, c)superimposing the model of the candidate agent on the model of theligand binding domain, and d) assessing whether the candidate agentmodel fits spatially into the ligand binding domain. Aspects a-d are notnecessarily carried out in the aforementioned order. Such methods mayfurther entail: performing rational drug design with the model of thethree-dimensional structure, and selecting a potential candidate agentin conjunction with computer modeling.

Additionally, one skilled in the art would appreciate that such methodsmay further entail: employing a candidate agent, so-determined to fitspatially into the ligand binding domain, in a biological activity assayfor Tie-2 kinase modulation, and determining whether said candidateagent modulates Tie-2 kinase activity in the assay. Such methods mayalso include administering the candidate agent, determined to modulateTie-2 kinase activity, to a mammal suffering from a condition treatableby Tie-2 kinase modulation, such as those described above.

Also, one skilled in the art would appreciate that compounds of theinvention can be used in a method of evaluating the ability of a testagent to associate with a molecule or molecular complex comprising aligand binding domain of a Tie-2 kinase. Such a method may becharacterized by the following aspects: a) creating a computer model ofa Tie-2 kinase binding pocket using structure coordinates obtained fromsuitable x-ray quality crystals of the Tie-2 kinase, b) employingcomputational algorithms to perform a fitting operation between the testagent and the computer model of the binding pocket, and c) analyzing theresults of the fitting operation to quantify the association between thetest agent and the computer model of the binding pocket.

Abbreviations and their Definitions

The following abbreviations and terms have the indicated meaningsthroughout:

Abbreviation Meaning Ac acetyl ACN acetonitrile ATP adenosinetriphosphate BNB 4-bromomethyl-3-nitrobenzoic acid Boc t-butyloxycarbonyl br broad Bu butyl ° C. degrees Celsius c- cyclo CBZCarboBenZoxy = benzyloxycarbonyl d doublet dd doublet of doublet dtdoublet of triplet DBU Diazabicyclo[5.4.0]undec-7-ere DCMdichloromethane = methylene chloride = CH₂Cl₂ DCE dichloroethylene DEADdiethyl azodicarboxylate DIC diisopropylcarbodiimide DIEAN,N-diisopropylethyl amine DMAP 4-N,N-dimethylaminopyridine DMFN,N-dimethylfonnamide DMSO dimethyl sulfoxide DVB 1,4-divinylbenzeneEEDQ 2-ethoxy-l-ethoxycarbonyl-1,2-dihydroquinoline EI Electron Impactionization Et ethyl Fmoc 9-fluorenylmethoxycarbonyl g gram(s) GC gaschromatography h or hr hour(s) HATUO-(7-Azabenzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate HMDS hexamethyldisilazane HOAc acetic acid HOBthydroxybenzotriazole HPLC high pressure liquid chromatography L liter(s)M molar or molarity m multiplet Me methyl mesyl methanesulfonyl mgmilligram(s) MHz megahertz (frequency) Min minute(s) mL milliliter(s) mMmillimolar mmol millimole(s) mol mole(s) MS mass spectral analysis MTBEmethyl t-butyl ether N normal or normality NBS N-bromosuccinimide NCSN-chlorosuccinimide nM nanomolar NMO N-methylmorpholine oxide NMRnuclear magnetic resonance spectroscopy PEG polyethylene glycol pEYpoly-glutamine, tyrosine Ph phenyl PhOH phenol PfP pentafluorophenolPfPy pentafluoropyridine PPTS Pyridinium p-toluenesulfonate Py pyridinePyBroP bromo-tris-pyrrolidino-phosphonium hexafluorophosphate q quartetRT Room temperature Sat'd saturated s singlet s- secondary t- tertiary tor tr triplet TBDMS t-butyldimethylsilyl TES triethylsilane TFAtrifluoroacetic acid THF tetrahydrofuran TMOF trimethyl orthoformate TMStrimethylsilyl tosyl p-toluenesulfonyl Trt triphenylmethyl μLmicroliter(s) μM Micromole(s) or micromolarSynthesis of Compounds

Schemes 1 and 2 depict general synthetic routes for compounds of theinvention and are not intended to be limiting. Specific examples aredescribed subsequently to these general synthetic descriptions. In thegeneralizations below, specific reaction conditions, for example, addedbases, acids, solvents, temperature, and the like were not described soas not to confuse the discussion. The general routes in conjunction withthe specific examples contain sufficient information to allow oneskilled in the art to synthesize compounds of the invention.

Referring to Scheme 1, an aromatic starting material, 1, having ortholeaving groups L₁ and L₂ (and assuming there may be optionalsubstituents on Ar), is combined with a first nucleophilic reagent Nu¹to afford intermediate 2. Examples of starting material 1 include, butare not limited to, 3,4-dichloro-1,2,5-thiadiazole,3,4-dichloro-pyrazine, 5,6-dichloro-2,3-dicyanopyrazine, and the like.Examples of first nucleophilic reagent Nu¹ include, but are not limitedto, Boc-piperazine, t-butyl 1-homopiperazine carboxylate,2,6-dimethyl-piperazine, 2,5-dimethyl-piperazine, and the like.Intermediates of type 2 may also be purchased, obviating the need forthe aforementioned synthetic conversion 1→2.

Leaving groups and nucleophiles are chosen to effect desiredregiochemical outcome of the particular synthesis, as is more fullyexemplified below. Nu¹ may be a preformed intermediate corresponding to“—X” in formula I, or a precursor to “—X,” in some instances as will beapparent from the examples below. Intermediate 2 is combined with asecond nucleophilic reagent, Nu², to afford intermediate 3. Again, insome instances Nu² may be a preformed intermediate corresponding to“—Y-L-Z” in formula I, or a precursor to “—Y-L-Z.” Examples of Nu²include, but are not limited to, pyridin-4-yl-methanol,3-(dimethylamino-phenyl)-methanol, and the like. Therefore, there may beneeded additional manipulation of Nu¹ and Nu² to synthesize compounds offormula I (as depicted), or intermediate 3 may itself be a compoundaccording to formula I. As mentioned, intermediate 3 may be converted tocompounds of formula I. Intermediate 3 may be purchased, made asdepicted in Scheme 1, or a commercially available or other startingmaterial is converted into 3, for example. This may entail, for example,a simple removal of a protecting group, reduction of an electrophilicmoiety to make either of Nu¹ or Nu², or in some cases a more complexmanipulation.

Scheme 2 shows one example of a conversion strategy 3→I to which any ofthe aforementioned scenarios would apply. Intermediate 3 (where Nu¹ hasa nucleophilic group thereon) is combined with an electrophile, E¹ toafford intermediate 4. An example of this strategy is where Nu¹ is apiperazine (where in formation of 3 one of the piperazine nitrogens isattached to the aromatic ring) and in conversion to 4, a ring —NH— is“capped” with electrofile E¹. Conversion of 4→5 may proceed in much thesame way, for example when Nu² has a free nucleophilic site, then anelectrophile E² may be added as depicted. There may be needed additionalmanipulation of 5 to synthesize compounds of formula I (as depicted), orintermediate 5 may itself be a compound according to formula I.

EXAMPLES

The following examples serve to more fully describe the manner of usingthe above-described invention, as well as to set forth the best modescontemplated for carrying out various aspects of the invention. It isunderstood that these examples in no way serve to limit the true scopeof this invention, but rather are presented for illustrative purposes.All references cited herein are incorporated by reference in theirentirety. Generally, each example is set out below with a correspondingmulti-step synthesis scheme. Following specific examples are lists ofcompounds that were made in a similar way.

Example 14-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide

4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acidtert-butyl ester: 1-Boc-piperazine (30.2 g, 165 mmol) was dissolved inDMF (30.0 mL) and heated to 100° C. 3,4-Dichloro-1,2,5-thiadiazole (7.5mL, 80 mmol) was added dropwise with stirring and the mixture heated at100° C. for 5.5 h. The reaction mixture was diluted with H₂O and the pHadjusted to 2.0 with 1N HCl. The resulting solids were filtered, washedwith H₂O and dried under vacuum to give 20.1 g (83%) of4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acidtert-butyl ester as a tan solid. ¹H NMR (DMSO-d6) 3.48 (m, 4H), 3.36 (m,4H), 1.42 (s, 9H) ppm. LC-MS (MH+)=205 (-Boc).

4-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid tert-butyl ester.4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acidtert-butyl ester (10.0 g, 33 mmol), pyridin-4-yl-methanol (6.9 g, 63mmol) and a solution of 1M potassium tert-butyl butoxide in tert-butylalcohol (60.0 mL, 60 mmol) were combined and stirred at room temperatureovernight. The reaction mixture is diluted with EtOAc and washed withH₂O (3×), sat'd NaCl (1×), dried (Na₂SO₄), and concentrated in vacuo.The crude product is purified by column chromatography (4:1hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 7.1 g (57%) of4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid tert-butyl ester. ¹H NMR (CDCl₃) 8.65 (d, 2H), 7.32 (d, 2H), 5.49(s, 2H), 3.55 (m, 8H) 1.48 (s, 9H) ppm. LC-MS (MH+)=378.

1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine,dihydrochloride salt.4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid tert-butyl ester (6.9 g, 18.3 mmol) was dissolved in 4M HCl indioxane (200 mL) and stirred at room temperature for 2 h. The resultingsuspension was diluted with EtOAc and the solids filtered, washed withEtOAc, and dried under high vacuum to give 6.15 g (96%) of1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine,dihydrochloride salt. ¹H NMR (D₂O) 8.59 (d, 2H), 7.92 (d, 2H), 5.66 (s,2H), 3.66 (m, 4H), 3.26 (m, 4H) ppm. LC-MS (MH+)=278.

4-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide.1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine,dihydrochloride salt (2.13 g, 6.1 mmol), dichloromethane (40 mL), andtriethylamine (2.5 mL, 17.9 mmol) were combined and cooled in anicebath. 1-Isocyanato-3,5-bis-trifluoromethyl-benzene (1.89 g, 7.4 mmol)in dichloromethane (10 mL) was added dropwise and the resulting mixturestirred overnight at room temperature. The reaction mixture was dilutedwith EtOAc and washed with sat'd NaHCO₃ (3×), sat'd NaCl (1×), dried(Na₂SO₄), and concentrated in vacuo. The crude product was purified bycolumn chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc)to give 2.6 g (80%) of4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid afterlyophilization from: H₂O—AcCN. ¹H NMR (CDCl₃) 8.62 (d, 2H), 7.84 (s,2H), 7.50 (s, 1H), 7.31 (d, 2H), 7.06 (s, 1H), 5.49 (s, 2H), 3.68-3.60(m, 8H) ppm. LC-MS (MH+)=533.

Example 2N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-1,4-diazepane-1-carboxamide

A mixture of t-butyl 1-homopiperazine carboxylate (45 mmol, 9 g) and DMF(50 ml) was heated to 100° C. 3,4-dichloro-1,2,5-thiadiazole (23 mmol,2.2 ml) was added dropwise to the mixture with stirring. The resultingmixture was stirred at 100° C. for 2 days. Mixture was quenched withice/water and extracted with ethyl acetate (3×). The combined organiclayer was washed with water (2×) and Sat. sodium chloride, dried oversodium sulfate, filtered and concentrated. The crude was purified on asilica column using 20% ethyl acetate/hexanes to give4-(4-chloro-[1,2,5]thiadiazol-3-yl)-[1,4]diazepane-1-carboxylic acidtert-butyl ester (5.8 g). The material thus obtained was converted intothe title compound by following the same procedures as in Example 1. ¹HNMR (CDCl3) 9.52 (s, 2H), 7.838 (s, 2H), 7.508 (s, 1H), 7.321-7.307 (d,2H), 6.769 (br. s, 1H), 5.464 (s, 2H), 3.925-3.851 (m, 4H), 3.820-3.790(t, 2H), 3.612-3.582 (t, 2H), 1.987-1.959 (m, 2H) ppm.

Example 32,6-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide

1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine.2,6-Dimethyl-piperazine (8.1 g, 71 mmol) was heated to 100° C. in DMF(8.0 ml). 3,4-Dichloro-1,2,5-thiadiazole (3.3 ml, 35 mmol) was added andthe mixture stirred at 100° C. for 3-4 h. The reaction mixture waspoured into H₂O and extracted with EtOAc (4×). The combined EtOAcextractions were washed with sat'd NaHCO₃ (1×), sat'd NaCl (1×), dried(Na₂SO₄), and concentrated in vacuo to give 7.9 g (97%) of1-(4-chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine which wasused without further purification. ¹H NMR (CDCl₃) 3.90-3.86 (m, 2H),3.05 (m, 2H), 2.52 (m, 2H), 1.12 (d, 6H) ppm. LC-MS (MH+)=233.

3,5-Dimethyl-1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine.1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-3,5-dimethyl-piperazine (7.9 g, 34mmol), pyridinyl-methanol (7.7 g, 70 mmol), potassium tert-butylbutoxide (11.4 g, 101 mmol) and tert-butyl alcohol (100 mL) werecombined and stirred at room temperature overnight. The reaction mixtureis diluted with H₂O (3×) and extracted with EtOAc (3×). The combinedEtOAc extractions are washed with sat'd NaHCO₃ (3×), sat'd NaCl (1×),dried (Na₂SO₄), and concentrated in vacuo. The crude product is purifiedby column chromatography (1:1 hexanes:EtOAc, followed by 49:1EtOAc:triethylamine, followed by 18:1:1 EtOAc:MeOH:triethylamine) togive 4.15 g (40%) of3,5-dimethyl-1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine.¹H NMR (CDCl₃) 8.62 (d, 2H), 7.30 (d, 2H), 5.48 (s, 2H), 4.07 (m, 2H),3.03 (m, 2H), 2.51 (m, 2H), 1.12 (d, 6H) ppm. LC-MS (MH+)=306.

2,6-Dimethyl-4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide.3,5-dimethyl-1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine(104 mg, 0.34 mmol), dichloromethane (1.0 mL), triethylamine (0.10 mL,0.43 mmol), and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (0.075 ml,0.43 mmol) are combined and stirred at room temperature overnight. Thereaction mixture was diluted with EtOAc and washed with H₂O (1×), sat'dNaHCO₃ (2×), sat'd NaCl (1×), dried (Na₂SO₄), and concentrated in vacuo.The crude product was purified by column chromatography (1:1hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 63 mg (33%) of2,6-dimethyl-4-[(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid afterlyophilization from H₂O—AcCN. ¹H NMR (CDCl₃) 8.67 (d, 2H), 7.91 (s, 2H),7.53 (s, 1H), 7.36 (d, 2H), 6.74 (s, 1H), 5.51 (s, 2H), 4.31 (m, 2H),4.10 (d, 2H), 3.11 (dd, 2H), 1.47 (d, 6H) ppm. LC-MS (MH+)=561.

The following compound compounds were prepared using a procedure as inExample 3:

N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamidewas prepared by employing 3,4-dichloro-1,2,5-thiadiazole and2-methyl-piperazine. ¹H NMR (CDCl3) 8.80 (br., d, 2H), 7.93 (s, 2H),7.66 (d, 2H), 7.53 (s, 1H), 6.90 (s, 1H), 5.64 (d, 2H), 4.43 (br., m,1H), 4.17 (d, 1H), 4.07 (d, 1H), 3.98 (d, 1H), 3.46 (td, 1H), 3.20 (dd,1H), 3.11 (td, 1H) 1.39 (d, 3H) ppm.

4-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,2,5-thiadiazol-3-yl]-N-[3,5-bis(trifluoro-methyl)phenyl]piperazine-1-carboxamidewas prepared by employing 3,4-dichloro-1,2,5-thiadiazole and1-aza-bicyclo[2.2.2]octan-3-ol. ¹H NMR (DMSO-d6) 9.81 (s, 1H), 9.31 (s,1H), 8.21 (s, 2H), 7.60 (s, 1H), 5.20 (m, 1H), 3.80-3.21 (m, 15H),2.00-1.75 (m, 4H) ppm.

4-[({4-[4-({[3,5-bis(trifluoromethyl)phenyl]amino}carbonyl)-piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]benzoicacid was prepared by employing 3,4-dichloro-1,2,5-thiadiazole and4-hydroxymethyl-benzoic acid. ¹H NMR (DMSO-d6) 9.24 (s, 1H), 8.19 (s,2H), 7.96 (d, 2H), 7.59 (s, 2H), 7.57 (s, 1H), 5.54 (s, 2H), 3.62-3.52(m, 8H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(piperidin-3-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamidewas prepared by employing 3,4-dichloro-1,2,5-thiadiazole andpiperidin-3-yl-methanol. ¹H NMR (DMSO-d6) 9.30 (s, 1H), 8.20 (s, 2H),7.60 (s, 1H), 4.32 (m, 2H), 3.63-3.51 (m, 8H), 1.99 (m, 7H), 1.82 (m,2H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-pyrrolidin-1-ylethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamidewas prepared by employing 3,4-dichloro-1,2,5-thiadiazole and2-pyrrolidin-1-yl-ethanol. ¹H NMR (DMSO-d6) 9.90 (br., s, 1H), 9.33 (s,1H), 8.20 (s, 2H), 7.60 (s, 1H), 4.70 (t, 2H), 3.70-3.34 (br., m, 12H),3.13 (br., m, 2H), 2.07-1.87 (br., m, 4H) ppm.

4-{4-[(2-amino-2-methylpropyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3,5-bis(trifluoro-methyl)phenyl]piperazine-1-carboxamidewas prepared by employing 3,4-dichloro-1,2,5-thiadiazole and2-amino-2-methyl-propan-1-ol. ¹H NMR (DMSO-d6) 9.29 (s, 1H), 8.21 (d,2H), 8.10 (br., s, 211, 7.60 (s, 1H), 4.42 (s, 2H), 3.65-3.53 (m, 8H),1.37 (s, 6H) ppm.

Example 4N-[3,5-bis(trifluoromethyl)phenyl]-2,6-dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide

To a round bottom flask equipped with a magnetic stir bar was added3,4-Dichloro-pyrazine (5 g, 33.8 mmol, 1.0 eq.), dry DMF (35 mL)2,6-Dimethyl-piperazine (7.86 g, 68.9 mmol, 2 eq). The reaction mixturewas heated to 100° C. and allowed to stir for 2 hours. After allowingthe reaction to return to room temperature water (200 mL) was added andthe product extracted with EtOAc (2×150 mL). The organic layer waswashed 2× water, 5×LiCl, 1× brine and dried over NaSO₄. After removingthe solvent in vacuo3′-Chloro-3,5-dimethyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl wasobtained as a yellow oil (4.8 g, 63%). This intermediate was thenconverted to the title compound by following the similar procedures asin Examples 3b and 3c. ¹H NMR (CDCl3) 8.87 (d, 2H), 7.92 (s, 2H), 7.83(m, 4H), 7.51 (d, 2H), 5.69 (s, 2H), 4.37 (m, 2H), 4.17 (d, 2H), 3.15(m, 2H), 1.48 (d, 5H) ppm.

The following compounds are prepared by using the procedure as inExample 4:

(2S)—N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamidewas prepared from 3,4-dichloro-pyrazine and 2-methyl-piperazine. ¹H NMR(CDCl3) 8.62 (d, 2H), 7.88 (s, 2H), 7.77 (d, 1H), 7.57 (d, 1H), 7.51 (s,1H), 7.33 (d, 2H), 6.64 (s, 1H), 5.44 (s, 2H), 4.32 (m, 1H), 4.21 (m,2H), 3.95 (d, 1H), 3.46 (m, 1H), 3.15 (dd, 1H), 3.03 (m, 1H), 1.32 (m,3H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-2,5-dimethyl-4-(3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl)piperazine-1-carboxamidewas prepared from 3,4-dichloro-pyrazine and 2,5-Dimethyl-piperazine. ¹HNMR (CDCl₃) 8.79 (d, 2H), 7.94-7.80 (s, 2H), 7.80 (d, 1H), 7.76 (s, 2H),7.49-7.46 (m, 2H), 7.08 (s, 1H), 5.64 (s, 2H), 4.68 (m, 2H), 3.92 (d,1H), 3.80 (d, 1H), 3.63-3.57 (m, 2H), 1.34 (d, 3H), 1.26 (d, 3H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]quinoxalin-2-yl}piperazine-1-carboxamidewas prepared from 2,3-dichloro-quinoxaline and 2-methyl-piperazine. ¹HNMR (CDCl3) 8.63 (d, 2H), 7.91 (s, 2H), 7.88 (m, 2H), 7.65 (m, 4H), 6.85(s, 1H), 5.63 (s, 2H), 4.40 (m, 3H), 4.01 (d, 1H), 3.48 (m, 1H), 3.31(dd, 1H), 3.08 (m, 1H), 1.38 (d, 3H) ppm.

Example 5N-[3,5-Bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)-oxy]pyrazin-2-yl}piperazine-1-carboxamide

3′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester. To a round bottom flask equipped with a magnetic stirbar was added 3,4-Dichloro-pyrazine (3 g, 20.1 mmol, 1.0 eq.), dry DMF(20 mL) and piperazine-1-carboxylic acid tert-butyl ester (7.3 g, 40mmol, 2 eq). The reaction mixture was heated to 90° C. and allowed tostir for 4 hours. After allowing the reaction to return to roomtemperature water (100 mL) was added and the product extracted with DCM(2×200 mL). The organic layer was washed 1 N HCl (2×) and brine (2×) anddried over NaSO₄. After removing the solvent the product was isolated asan orange oil (6 g, 80%).

3′-(Pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. To a round bottom flask equipped with a magneticstir bar was added3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester (7.89 g, 26.4 mmol, 1.0 eq.), pyridin-4-yl-methanol(3.74 g, 34.3 mmol, 1.3 eq) and 1M potassium tert-butyl butoxide int-butanol (72 ml, 72 mmol, 2.7 eq). The reaction was then stirredovernight at room temperature after which the solvent was removed. Thesolid was then diluted with EtOAc, washed 3× with water, 2×NaHCO₃, 2×with brine, and dried over NaSO₄. Purification was then accomplished oncolumn chromatography with the eluent being 1:2 ethyl acetate/hexane and2% TEA. Removal of the solvent resulted in the title compound as a creamsolid (6.98 g, 33% yield).

3′-(Pyridin-4-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl. To around bottom flask equipped with a magnetic stir bar was added4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acidtert-butyl ester (6.98 g, 18.8 mmol, 1.0 eq) and 4M HCl/Dioxane. Thereaction was then allowed to stir for 1 hour at room temperature. Theresulting precipitate was filtered, washed with hexane, and dried invacuo to give the title compound as a white solid (5.12 g, 89% yield).

N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide.To a round bottom flask equipped with a magnetic stir bar was added3′-(pyridin-4-ylmethoxy)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (0.3 g,0.97 mmol, 1.0 eq.), dry CH₂Cl₂ (3 mL), triethyl amine (TEA) (0.54 g,0.4 mL, 5.1 mmol, 5 eq) and was then cooled in an ice bath.1-Isocyanato-3,5-bis-trifluoromethyl-benzene (0.29 g, 0.2 ml, 1.2 mmol,1.2 eq.) was then added drop wise to the reaction mixture. Totalreaction time was 3 hours at which point the reaction was diluted with3× the volume EtOAc. This solution was then washed 3× with NaHCO₃ and 2×with brine. The organic layer was dried with Na₂SO₄, concentrated, andthe solid was columned with a Biotage system using a gradient. Theinitial eluent was 1:1 ethyl acetate/hexane followed by an eluent 3:1ethyl acetate/hexane. The solvent was then removed and dried under highvacuum to yield the title compound (0.16 g, 32% yield) as a solid. ¹HNMR (CDCl3) 8.63 (d, 2H), 7.90 (s, 2H), 7.81 (d, 1H), 7.62 (d, 1H), 7.54(s, 1H), 7.34 (d, 2H), 7.26 (s, 2H), 6.78 (s, 1H), 5.48 (s, 2H), 3.67(m, 8H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-1,4-diazepane-1-carboxamidewas prepared as in example 5 starting from t-butyl 1-homopiperazinecarboxylate (25 mmol, 5 g) and 2,3-dichloropyrazine. ¹H NMR (CDCl3)8.616-8.603 (d, 2H), 7.821 (s, 2H), 7.692-7.684 (d, 1H), 7.482 (s, 1H),7.427-7.420 (d, 1H), 7.326-7.312 (d, 2H), 6.962 (s, 1H), 5.416 (s, 2H),3.969-3.912 (m, 4H), 3.798-3.784 (t, 2H), 3.584-3.555 (t, 2H),1.951-1.924 (t, 2H) ppm.

Example 62-Methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide

3′-Chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. 3-Methyl-piperazine-1-carboxylic acid tert-butylester (5.0 g, 25 mmol), 2,3-dichloropyrazine (1.3 mL, 12.5 mmol), andDMF (5.0 mL) were combined and heated to 100 C overnight with stirring.The reaction mixture was poured into H₂O and extracted with EtOAc (3×).The combined EtOAc extractions were washed with sat'd NaHCO₃ (2×), sat'sNaCl (1×), dried (Na₂SO₄), and concentrated in vacuo. The crude productwas purified by column chromatography (4:1 hexanes:EtOAc) to give 1.76 g(45%) of3′-chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. ¹H NMR (CDCl₃) 8.08 (d, 1H), 7.86 (d, 1H),4.22-3.76 (complex m, 3H), 3.48-3.17 (complex m, 4H), 1.48 (s, 9H), 1.19(d, 3H) ppm. LC-MS (MH+)=257 (-t-butyl).

2-Methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester.3′-Chloro-2-methyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (1.88 g, 6.0 mmol), pyridin-4-yl-methanol (1.35 g,12.4 mmol) and a solution of 1M potassium tert-butyl butoxide intert-butyl alcohol (14 mL, 14 mmol) were combined and stirred at roomtemperature overnight. The reaction mixture is diluted with H₂O andwashed with EtOAc (3×). The combined EtOAc extractions were washed with6% NaHCO₃ (2×), sat's NaCl (1×), dried (Na₂SO₄), and concentrated invacuo. The crude product was purified by column chromatography (4:1hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 1.89 g (81%) of2-methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. ¹H NMR (CDCl₃) 8.06 (d, 2H), 7.75 (d, 1H), 7.51(d, 1H), 7.30 (d, 2H), 5.42 (s, 2H), 4.52 (m, 1H), 4.11-3.81 (complex m,3H), 3.36-3.11 (complex m, 3H), 1.48 (s, 9H), 1.17 (d, 3H) ppm. LC-MS(MH+)=386.

2-Methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide.2-Methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (103 mgs, 0.27 mmol) was dissolved indichloromethane (1.5 mL) to which was added TFA (2.0 mL) and the mixturestirred at room temperature for 1 hr until Boc removal was complete. Thereaction mixture was concentrated in vacuo and redissolved indichloromethane (1.0 mL) to which was added triethylamine (0.2 mL, 1.43mmol) and 1-isocyanato-3,5-bis-trifluoromethyl-benzene (0.055 ml, 0.32mmol). The mixture was stirred at room temperature overnight. Thereaction mixture was concentrated in vacuo and the resulting residuepurified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3hexanes:EtOAc) to give 98.9 mgs (69%) of2-methyl-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid afterlyophilization from H₂O—AcCN. ¹H NMR (CDCl₃) 8.77 (d, 2H), 7.94 (s, 2H),7.82 (d, 1H), 7.71 (d, 2H), 7.52 (d, 1H), 7.49 (s, 1H), 7.23 (s, 1H),5.62 (s, 2H), 4.60 (m, 1H), 4.01 (m, 1H), 3.97-3.86 (m, 2H), 3.52-3.45(m, 2H), 3.34 (m, 1H), 1.26 (d, 3H) ppm. LC-MS (MH+)=541.

Example 71-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylicacid (3-trifluoromethyl-phenyl)-amide

1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid ethylester. Piperidine-4-carboxylic acid ethyl ester (14.0 mL, 91 mmol) wasdissolved in DMF (15.0 mL) and heated to 100 C.3,4-Dichloro-1,2,5-thiadiazole (4.0 mL, 42 mmol) was added and themixture heated at 100 C. for 4 h. The reaction mixture was poured into1N HCl and extracted with EtOAc (4×). The combined EtOAc extractionswere washed with H₂O (1×), sat'd NaCl (1×), dried (Na₂SO₄), andconcentrated in vacuo to give 12.3 g (105%) of1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid ethylester which was used without further purification. ¹H NMR (CDCl₃)4.30-4.13 (m, 2H), 4.06-3.93 (m, 2H), 3.12-2.99 (m, 2H), 2.59 (m, 1H),2.03 (m, 4H), 1.42-1.26 (m, (3H) ppm. LC-MS (MH+)=276.

1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid.1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid ethylester (12.3 g, 45 mmol) was dissolved in EtOH (70 mL) to which was added5N NaOH (15 mL). The mixture was stirred at room temperature for 2 h,then concentrated in vacuo. The resulting aqueous solution was furtherdiluted with H₂O, washed with EtOAc (3×) and acidified to pH 2.0 withconc'd HCl. The resulting precipitate was filtered, washed with H₂O anddried under high vacuum to give 8.44 g (77%) of1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid. ¹H NMR(CDCl₃) 3.97-3.92 (m, 2H), 3.03 (m, 2H), 2.59 (m, 1H), 2.06 (m, 2H),1.93 (m, 2H) ppm. LC-MS (M−)=246.

1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylicacid. 1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidine-4-carboxylic acid(7.99 g, 32 mmol), pyridin-4-yl-methanol (7.39 g, 68 mmol) and asolution of 1M potassium tert-butyl butoxide in tert-butyl alcohol (100mL, 100 mmol) were combined and stirred at room temperature overnight.The reaction mixture is diluted with H₂O (500 mL) and washed with EtOAc(3×). The aqueous phase is concentrated to ˜250 mL and acidified to pH5-6 with conc'd HCl. The resulting solids are filtered, washed with H₂Oand dried under high vacuum to give 6.04 g (59%) of1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylicacid. ¹H NMR (DMSO-d6) 8.57 (d, 2H), 7.41 (d, 2H), 5.51 (s, 2H), 4.03(m, 2H), 3.00 (m, 2H), 2.46 (m, 1H), 1.91 (m, 2H), 1.63 (m, 2H) ppm.LC-MS (M−)=319.

1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylicacid (3-trifluoromethyl-phenyl)-amide.1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylicacid (280 mg, 0.87 mmol), HATU (328 mg, 0.86 mmol), DMF (1.5 mL) andDIEA (0.5 mL, 3.87 mmol) were combined and vortexed until a homogeneousmixture was obtained. 3-Trifluoromethyl-phenylamine (0.109 mL, 0.87mmol) was added and the resulting mixture stirred at room temperatureovernight. The reaction mixture was diluted with EtOAc and washed withsat'd NaHCO₃ (3×), sat'd NaCl (1×), dried (Na₂SO₄), and concentrated invacuo. The crude product was purified by column chromatography (4:1hexanes:EtOAc, followed by 1:1 hexanes:EtOAc) to give 100 mg (25%) of1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidine-4-carboxylicacid (3-trifluoromethyl-phenyl)-amide as a white solid afterlyophilization from H₂O—AcCN. ¹H NMR (CD₃OD) 8.54 (d, 2H), 8.02 (s, 1H),7.74 (d, 1H), 7.51-7.46 (m, 3H), 7.36 (d, 1H), 5.57 (s, 2H), 4.32 (m,2H), 3.00 (m, 2H), 2.64 (m, 1H), 1.96-1.90 (m, 4H) ppm. LC-MS (MH+)=464.

Example 81-(3,5-Bis-trifluoromethyl-phenyl)-3-{1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidin-4-ylmethyl}-urea

[1-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-carbamic acidtert-butyl ester. 4-(tert-Butoxycarbonylaminomethyl)piperidine (3.96 g,18.4 mmol) was dissolved in DMF (3.5 ml) and heated to 100° C.3,4-Dichloro-1,2,5-thiadiazole (0.85 mL, 9.0 mmol) was added and themixture stirred at 100° C. overnight. DIEA (2.0 ml, 11.5 mmol) was addedand heating at 100° C. continued until the reaction was complete (˜3 h).The reaction mixture was diluted with 1N HCl and extracted with EtOAc(3×). The combined EtOAc extractions were washed with H2O (1×), sat'dNaCl (1×), dried (MgSO4), and concentrated in vacuo to give 2.39 g (80%)of [1-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperidin-4-ylmethyl]-carbamicacid tert-butyl ester as a tan solid. ¹H NMR (DMSO-d6) 6.91 (t, 1H),3.87 (m, 2H), 2.84 (m, 4H), 1.69 (m, 2H), 1.56 (m, 1H), 1.36 (s, 9H),1.24 (m, 2H) ppm. LC-MS (MH+)=333.

{1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidin-4-ylmethyl}-carbamicacid tert-butyl ester. A mixture of the product from step 1 (0.47 mmol,155 mg), 1M potassium t-butoxide in t-butanol (1.5 ml), and 4-pyridylcarbinol (1.33 mmol, 0.145 g) was stirred at room temperature overnight.The mixture was quenched with ice/water and extracted with ethyl acetate(2×). The combined organic layer was washed with water (3×) and Sat.NaCl, dried over sodium sulfate and concentrated. The crude product waspurified on silica column using 75% ethyl acetate/hexanes, affording 70mg of product.

C-{1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperidin-4-yl}-methylaminedihydrochloride. The product (70 mg) obtained in step 2 was dissolved in4M HCl in 1,4-dioxane (30 ml), and stirred for 2 hours. The mixture wasconcentrated. The residue was diluted with EtOAc and the solidsfiltered, washed with EtOAc, and dried under high vacuum to give 50 mgof the amine product as the HCl salt.

N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperidin-4-yl)methyl]urea.A mixture of the product in step 3 (0.12 mmol, 50 mg), DCM (10 ml), TEA(0.42 mmol, 59 ul), and 3,5-bis(trifluoromethyl)-phenyl isocyanate (0.13mmol, 23 ul) was stirred at room temperature overnight. After removal ofsolvent, the residue was diluted with EtOAc, stirred and filtered. Thefiltrate was concentrated and then purified on silica column using 75%ethyl acetate/hexanes to yield 22 mg of the title compound. ¹H NMR(DMSO-d6) 9.207 (s, 1H), 8.607-8.593 (d, 2H), 8.083, (s, 2H), 7.55 (s,1H), 7.438-7.423 (d, 2H), 6.621-6.592 (t, 1H), 5.520 (s, 2H),4.163-4.131 (d, 2H), 3.302-3.031 (t, 2H), 2.909-2.850 (t, 2H),1.743-1.713 (m, 3H), 1.274-1.243 (m, 2H) ppm.

Example 9N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-1,4-diazepane-1-carboxamide

4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-[1,4]diazepane-1-carboxylic acidtert-butyl ester. A mixture of t-butyl 1-homopiperazine carboxylate (45mmol, 9 g) and DMF (50 ml) was heated to 100° C.3,4-dichloro-1,2,5-thiadiazole (23 mmol, 2.2 ml) was added to themixture and stirred at 100° C. for 2 days. The mixture was quenched withice/water and extracted with ethyl acetate (3×). The combined organiclayer was washed with water (2×) and brine, dried over sodium sulfate,filtered and concentrated. The crude was purified on silica column using20% ethyl acetate/hexanes to give 5.8 g of product.

4-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-[1,4]diazepane-1-carboxylicacid tert-butyl ester. The product obtained in the paragraph above wasmixed with 1M potassium t-butoxide in t-butanol (40 ml) and4-pyridylcarbinol (36.6 mmol, 4 g), and stirred at room temperatureovernight. The mixture was quenched with ice/water and extracted withethyl acetate (2×). The combined organic layer was washed with water(3×) and Sat. NaCl, dried over sodium sulfate and concentrated. Thecrude product was column purified on silica using 75% ethylacetate/hexanes to give 3.68 g of the title compound.

1-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-[1,4]diazepanedihydrochloride. The product (3.68 g) obtained as described in theparagraph above was dissolved in 4M HCl in 1,4-dioxane (100 ml), andstirred for 4 hours. The mixture was concentrated. The residue wasdiluted with EtOAc and the solids filtered, washed with EtOAc, and driedunder high vacuum to give 3.3 g of the amine product as the HCl salt.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-1,4-diazepane-1-carboxamide.A mixture of the product obtained as described in the paragraph above(0.41 mmol, 0.15 g), DCM (10 ml), TEA (1 mmol, 140 ul), and3,5-bis(trifluoromethyl)-phenyl isocyanate (0.5 mmol, 86 ul) was stirredat room temperature overnight. After removal of solvent, the residue wasdiluted with EtOAc, stirred and filtered. The filtrate was concentratedand then purified on silica column using 75% ethyl acetate/hexanes toyield 150 mg of the title compound. ¹H NMR (CDCl3) 9.52 (s, 2H), 7.838(s, 2H), 7.508 (s, 1H), 7.321-7.307 (d, 2H), 6.769 (br. s, 1H), 5.464(s, 2H), 3.925-3.851 (m, 4H), 3.820-3.790 (t, 2H), 3.612-3.582 (t, 2H),1.987-1.959 (m, 2H) ppm.

Example 10N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[3-(dimethylamino)phenyl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide

4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine hydrochloride. To a roundbottom flask equipped with a magnetic stir bar was added4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acidtert-butyl ester (10 g, 32 mmol, 1.0 eq, prepared as Example 1a) and 4MHCl/Dioxane. The reaction was allowed to stir at room temperature for 2hour. The resulting precipitate was filtered, washed with EtOAc threetimes, dried in vacuo to give4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine hydrochloride (7.8 g) asa white solid.

1-(4-Chloro-[1,2,5]thiadiazol-3-yl)piperazine hydrochloride.4-(4-Chloro-[1,2,5]thiadiazol-3-yl)piperazine-1-carboxylic acidtert-butyl ester (1.0 g, 3.28 mmol) was suspended in 10 mL of 4 M HCl indioxane. The suspension was stirred overnight and the solid material wasremoved by filtration. The solid was washed three times with 15 mL ethylacetate and dried under vacuum. 756 mg of white powder was obtained.

4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide. To a round bottom flask equippedwith a magnetic stir bar was added4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine (7.8 g, 32.6 mmol, 1.0eq.), dry CH₂Cl₂ (130 mL), triethyl amine (11.66 g, 16 mL, 115.2 mmol,3.5 eq). To this mixture cooled in an ice bath was added1-isocyanato-3,5-bis-trifluoromethyl-benzene (11.6 g, 7.9 ml, 45 mmol,1.4 eq.) dissolved in dry CH₂Cl₂ (20 mL) dropwise. The resulting mixturewas allowed to warm up to room temperature with stirring. After stirringfor 3 hour, the reaction mixture was diluted with EtOAc. This solutionwas then washed with aqNaHCO₃, and brine. The organic layer was driedwith Na₂SO₄, concentrated. The residue was purified by columnchromatography using acetate/hexane (1:1 to 3:1), affording4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (11.8 g, 79% yield) as a solid.

4-[4-(3-Dimethylamino-benzyloxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide. To a round bottom flaskequipped with a magnetic stir bar was added4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (0.1 g, 0.21 mmol, 1.0 eq.),(3-Dimethylamino-phenyl)-methanol (0.065 g, 0.062 mL, 0.43 mmol, 2.0 eq)and 1M potassium tert-butyl butoxide in t-butanol (0.65 ml, 0.65 mmol,3.0 eq). The mixture was stirred at room temperature overnight. Afterremoval of solvent in vacuo, the crude mixture was purified onpreparative HPLC, affording the title compoundN-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[3-(dimethylamino)phenyl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamideas a white solid (0.06 g, 55% yield). ¹H NMR (DMSO-d6) 9.23 (s, 1H),8.18 (s, 2H), 7.59 (s, 1H), 7.22 (m, 1H), 6.89 (s, 1H), 6.78 (m, 2H),5.39 (m, 4H), 3.61 (m, 4H), 3.53 (m, 4H), 2.92 (s, 6H) ppm.

The following compounds were prepared using the procedure as in Example10 from 4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoro-methyl-phenyl)-amide:

N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(3-thienylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide.¹H NMR (CDCl3) 7.88 (s, 2H), 7.53 (s, 1H), 7.40-7.39 (m, 1H), 7.36 (dd,1H), 7.17 (dd, 1H), 6.67 (s, 1H), 5.48 (s, 2H), 3.64-3.61 (m, 8H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-(1H-indol-5-yloxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide.To a round bottom flask equipped with a magnetic stir bar was added4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (0.1 g, 0.21 mmol, 1.0 eq.),H-Indol-5-ol (0.0579 g, 0.43 mmol, 2.0 eq) and 1M potassium tert-butylbutoxide in t-butanol (0.65 ml, 0.65 mmol, 3.0 eq). The reaction mixturewas stirred at 70° C. for 2 hours. After removal of solvent in vacuo,the crude mixture was purified on preparative HPLC, affording the titlecompoundN-[3,5-bis(trifluoromethyl)phenyl]-4-[4-(1H-indol-5-yloxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamideas a white solid (0.04 g, 33% yield). ¹H NMR (DMSO-d6) 9.17 (s, 1H),9.09 (s, 1H), 8.15 (s, 2H), 7.81 (d, 1H), 7.53 (m, 2H), 6.96 (d, 1H),6.75 (d, 1H), 6.63 (d, 1H), 3.53 (m, 4H), 3.02 (m, 4H) ppm.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{1,1-dioxido-4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide.To a round bottom flask equipped with a magnetic stir bar was added4-[4-(Pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid(3,5-bis-trifluoromethyl-phenyl)-amide (0.1 g, 0.19 mmol, 1.0 eq.)and dry CH₂Cl₂ (20 mL). The reaction was then cooled in using an icebath followed by the addition of MCPBA (0.039 g, 0.23 mmol, 1.2 eq). Thereaction was then allowed to slowly return to room temperature at whichpoint the solvent was removed. The white solid was dissolved in DMSO (2mL) and purified by preparative HPLC. The fraction containing thedesired product was dried by lyophylization to give a white solid (1.5mg, 1.5% yield). ¹H NMR (DMSO-d6) 9.25 (s, 1H), 8.29 (d, 2H), 8.21 (s,2H), 7.62 (s, 1H), 7.56 (d, 2H), 5.46 (d, 2H), 3.65 (m, 8H) ppm.

Example 11N-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide

3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. To a solution of 1-Boc-piperazine (8 mmol, 1.5 g)and anhydrous tetrahydrofuran cooled at −45° C. was added5,6-dichloro-2,3-dicyanopyrazine (4 mmol, 800 mg). The mixture wasstirred at −45° C. for 1.5 hours. Reaction mixture was concentrated andstirred in EtOAc, filtered and concentrated. The crude material waspurified on silica column using 30% EtOAc/hexanes to yield3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (640 mg).

5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. To a solution of 4-pyridylcarbinol (0.44 mmol, 45mg) and anhydrous tetrahydrofuran (3 ml) cooled at 0° C. was added LDA(2M, 0.6 mmol, 300 ul). The mixture was stirred at 0° C. for 15 minutes.A solution of3′-Chloro-5′,6′-dicyano-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (0.29 mmol, 100 mg) in THF (2 ml) was then addedto the cold mixture and stirred at 0° C. for 1 hour. Reaction mixturewas poured onto 0.5M acetic acid and extracted with ethyl acetate. Thecrude product was purified by column chromatograph on silica using 70%EtOAc/hexanes to yield product5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (100 mg).

N-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]-pyrazin-2-yl}piperazine-1-carboxamide.A mixture of5′,6′-Dicyano-3′-(pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (100 mg) and 30% TFA in DCM (11 ml) was stirredfor 2 hours. The mixture was concentrated in vacuo to dryness. To theresidue was added DCM (5 ml), TEA (0.31 mmol, 51 ul), and3,5-bis(trifluoromethyl)phenyl isocyanate (0.15 mmol, 26 ul). Theresulting mixture was stirred at room temperature for 3 hours. Afterconcentrated in vacuo, the crude product was purified by column onsilica using 70% EtOAc/Hexanes to give the productN-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide.¹H NMR (CD3OD) 8.594 (s, 2H), 8.073 (s, 2H), 7.555-7.534 (m, 3H), 5.584(s, 2H), 4.043-4.029 (m, 4H), 3.739-3.713 (m, 4H) ppm.

Example 12N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-ylmethyl)oxy]phenyl}piperazine-1-carboxamide

4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester. To asolution of 2-(1-piperizine)phenol (56 mmol, 10 g) and 1,4-dioxane (120ml) was added water (120 ml), sodium bicarbonate (56 mmol, 4.7 g), anddi-t-butyl dicarbonate (56 mmol, 12.2 g). The mixture was stirred atroom temperature overnight. The resulting precipitate from the mixturewas filtered and washed with water, and then dissolved in ethyl acetateand washed with brine. The organic layer was concentrated in vacuo togive 4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester(15.5 g).

4-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester. A mixture of4-(2-Hydroxy-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (18mmol, 5 g), DMF (40 ml) and cesium carbonate (40 mmol, 13 g) was stirredat room temperature for 15 minutes, followed by addition of 4-picolylchloride hydrochloride (18 mmol, 2.953 g). The resulting mixture wasstirred at room temperature overnight. The reaction mixture was pouredonto ice/water and extracted with ethyl acetate (3×). The combinedorganic layer was washed with Sat. NaCl. The crude product was purifiedon silica column using 75% EtOAc/hexanes to give4-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazine-1-carboxylic acidtert-butyl ester (4.5 g).

1-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazine dihydrochloride. The aboveproduct (4.5 g) was dissolved in 1,4-dioxane (25 ml) followed byaddition of 4M HCl in dioxane (75 ml), and stirred for 3 hours. Theresulting precipitate was filtered, washed with ethyl acetate and driedin vacuo to give 1-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazinedihydrochloride.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-ylmethyl)oxy]phenyl}-piperazine-1-carboxamide.A mixture of 1-[2-(Pyridin-4-ylmethoxy)-phenyl]-piperazinedihydrochloride (0.3 mmol, 100 mg), DCM (5 ml), TEA (1 mmol, 139 ul),and 3,5-bis(trifluoromethyl)phenyl isocyanate (0.6 mmol, 104 ul) wasstirred at room temperature overnight. The mixture was concentrated invacuo and purified on silica column using 80% EtOAc/hexanes to giveN-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-ylmethyl)oxy]phenyl}piperazine-1-carboxamide.¹H NMR (CDCl3) 8.599-8.586 (d, 2H), 7.855 (s, 2H), 7.559-7.452 (d, 2H),7.390-7.377 (d, 2H), 7.021-6.888 (m, 4H), 5.146 (s, 2H), 3.728-3.704 (m,4H), 3.149-3.125 (m, 4H) ppm.

Example 13N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-fluoropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide

2-Fluoro-4-pyridinemethanol. This compound was prepared according toPesti's procedure (J. Org. Chem. 2000, 65, 7718-7722). A mixture of2-Fluoro-4-methyl-pyridine (1.99 g, 17.9 mmol), N-Chlorosuccinimide(3.59 g, 26.9 mmol), benzoyl peroxide (99.0 mg, 0.409 mmol), and aceticacid (60 μL, 1.05 mmol) in acetonitrile (10 mL) was heated at reflux for90 min. The mixture was allowed to cool to room temperature, then pouredinto water (8 mL) and extracted with EtOAc. The organic phase was washedwith brine, dried over MgSO₄, and concentrated in vacuo at 35° C. A redoil was obtained (2.6 g). ¹H NMR revealed a 1.7:1 molar ratio of4-chloromethyl-2-fluoro-pyridine to 2-fluoro-4-methyl-pyridine. Thecrude material was carried to the hydrolysis step without furtherpurification. The crude material obtained (2.6 g, 12.1 mmol), andpotassium carbonate (2.4 g, 17.4 mmol) were suspended in water (30 mL)and heated at reflux for 2 h. The mixture was allowed to cool to roomtemperature and the phases were separated. The oily phase was furtherextracted with water. The combined aqueous phases were washed withhexanes and extracted with EtOAc. The combined organic phases were driedover MgSO₄ and concentrated in vacuo to yield2-fluoro-4-pyridinemethanol (514 mg, 22.5% over 2 steps, 95 LC area %)as an off white solid.

3′-Hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester. To a solution of3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester (1.85 g, 6.19 mmol, prepared in Example 5a) in DMSO (6mL) was added a 2.5M aqueous solution of NaOH (30 mL). The resultingsuspension was heated to reflux for 12 h before allowing to cool to roomtemperature. The suspension was then diluted with water (20 mL),acidified to pH=5 with 6M HCl, and extracted with EtOAc. The organicphase was concentrated in vacuo and the resulting solids were purifiedby flash chromatography (silica gel, 5.5:1 EtOAc:Hexanes). Product3′-Hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester was obtained as white solids (538 mg, 31.0%).

3′-(2-Fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester. To a suspension of3′-hydroxy-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester (304 mg, 1.08 mmol), 2-Fluoro-4-pyridinemethanol (138mg, 1.08 mmol), and triphenylphosphine (286 mg, 1.09 mmol) in THF (5 mL)was added diethyl azidocarboxylate (210 mg, 1.21 mmol) dropwise. Theresulting clear brown solution was stirred at room temperature for 16 h,then concentrated in vacuo. The crude solids were purified by flashchromatography (silica gel, 1:2 EtOAc:Hexanes). Product3′-(2-fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester was obtained as white solid (113 mg, 26.9% yield).

N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-fluoropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide.A 20% solution of TFA in dichloromethane was added to3′-(2-fluoro-pyridin-4-ylmethoxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid tert-butyl ester (113 mg, 0.290 mmol). The solution was stirred atroom temperature for 1 h until complete de-protection was evident byLCMS, then concentrated in vacuo. The resulting solid was diluted withdichloromethane (3 mL). Triethylamine (193 mg, 1.91 mmol) was added andassured bacisity with pH paper. The solution was cooled to −5° C. and1-isocyanato-3,5-bis-trifluoromethyl-benzene (88.6 mg, 0.347 mmol) wasadded dropwise. After the addition was complete, the solution wasstirred at −5° C. for 5 min, then allowed to warm up to room temperatureand stirred for an additional 3 h. The solution was then diluted withEtOAc (20 mL), washed with satd. NaHCO_(3(aq)) and brine, dried overMgSO₄ and concentrated in vacuo. The crude solids were dissolved in MeOHand purified by preparative HPLC (50 mM NH₄OAc_((aq)), acetonitrilesolvent system). The product was isolated by lyophilization of purefractions yieldingN-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-fluoropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide(50.5 mg, 32.0% yield). ¹H NMR (CDCl3) 8.24 (d, 1H), 7.91 (s, 2H), 7.82(d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.22 (d, 1H), 6.98 (s, 1H), 6.73(d, 1H), 5.51 (s, 2H), 3.70-3.65 (m, 8H) ppm.

Example 14N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide

4-(Chloromethyl)-2-chloropyridine. A mixture of2-chloro-4-methyl-pyridine (7.28 g, 57.1 mmol), N-Chlorosuccinimide(11.4 g, 85.3 mmol), benzoyl peroxide (276 mg, 1.13 mmol), and aceticacid (200 μL, 3.5 mmol) in acetonitrile (30 mL) was heated at reflux for2.5 h. The mixture was allowed to cool to room temperature, then pouredinto water (10 mL) and extracted with EtOAc. The organic phase waswashed with brine, dried over MgSO₄, and concentrated in vacuo at 35°C., yielding the crude product of 4-(chloromethyl)-2-chloropyridine(9.25 g) as an oil. The crude oil was carried on to the hydrolysis stepwithout further purification.

2-Chloro-4-pyridinemethanol. The crude product of4-(chloromethyl)-2-chloropyridine (9.25 g), and potassium carbonate (9.5g, 68.7 mmol) were suspended in water (100 mL) and heated at reflux for2.5 h. The mixture was allowed to cool to room temperature and thephases were separated. The oily phase was further extracted with water.The combined aqueous phases were washed with hexanes and extracted withEtOAc. The combined EtOAc phases were dried over MgSO₄ and concentratedin vacuo to yield 2-Chloro-4-pyridinemethanol as an off white solid (762mg, 9.3% yield over 2 steps).

3′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide. To a solution of3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acidtert-butyl ester (3.7 g, 12.4 mmol, prepared in Example 5a) anddichloromethane (20 mL) was added anhydrous 4M HCl/Dioxane (20 mL). Thesolution was stirred for 1 h until complete de-protection was evident byLCMS. The solution was concentrated in vacuo, which was thenre-dissolved in dichloromethane (50 mL). Triethylamine (3.78 g, 37.4mmol) was added and the solution was cooled to 0° C. before dropwiseaddition of 1-isocyanato-3,5-bis-trifluoromethyl-benzene (3.70 g, 14.5mmol) with stirring. After completion of addition the solution wasallowed to warm up to room temperature and stirred for 1 h. The reactionmixture was diluted with EtOAc (150 mL), then washed with saturatedsodium bicarbonate, and brine. The organic phase was dried over MgSO₄and concentrated in vacuo to yield3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (5.6 g, 100%) as a white solid.

N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide.To a solution of3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (115 mg, 0.254 mmol) and 1Msolution of potassium tert-butoxide in tert-butanol (0.80 mL, 0.80 mmol)was added 2-Chloro-4-pyridinemethanol (81.8 mg, 0.568 mmol). Theresulting suspension was stirred at room temperature for 15 h. The crudereaction mixture was diluted with methanol and purified by preparativeHPLC (50 mM NH₄OAc_((aq)), Acetonitrile system). The product wasisolated by lyophilization of pure fractions yieldingN-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4-yl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide(29.9 mg, 21% yield). ¹H NMR (CDCl3) 8.41 (d, 1H), 7.91 (s, 2H), 7.82(d, 1H), 7.61 (d, 1H), 7.54 (s, 1H), 7.39 (s, 1H), 6.70 (s, 1H), 5.47(s, 2H), 3.70-3.65 (m, 8H) ppm.

Example 154-[4-(2-Fluoro-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide

To a solution of4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (117.7 mg, 0.265 mmol, preparedin Example 10b) and 1M solution of potassium tert-butoxide intert-butanol (0.75 mL, 0.75 mmol) was added 2-Fluoro-4-pyridinemethanol(65.6 mg, 0.516 mmol, prepared in Example 15a). The resulting suspensionwas stirred at room temperature for 2 h. The crude reaction mixture wasdiluted with methanol and purified by preparative HPLC (50 mMNH₄OAc_((aq)), Acetonitrile system). The pure fractions were combinedand the acetonitrile was removed in vacuo. The remaining aqueoussolution was made basic with NaHCO₃ and the free based product wasextracted into EtOAc. The organic phase was concentrated in vacuo, andthe solids were re-dissolved in acetonitrile/water and lyophilized toobtain pure product4-[4-(2-Fluoro-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide. (19.0 mg, 13.5% yield). ¹HNMR (CDCl3) 8.26 (d, 1H), 7.88 (s, 2H), 7.53 (s, 1H), 7.22 (d, 1H), 6.98(s, 1H), 6.88 (s, 1H), 5.53 (s, 2H), 3.73-3.50 (m, 8H) ppm.

Example 16N-[3,5-Bis(trifluoromethyl)phenyl]-4-(4-{[(2-chloropyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

To a solution of4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (103.7 mg, 0.226 mmol, preparedin Example 10b) and 1M solution of potassium tert-butoxide intert-butanol (0.70 mL, 0.70 mmol) was added 2-chloro-4-pyridinemethanol(64.5 mg, 0.448 mmol, prepared in Example 16a). The resulting suspensionwas stirred at room temperature for 2 h. The crude reaction mixture wasdiluted with methanol and purified by preparative HPLC (0.1% TFA inwater, 0.1% TFA in acetonitrile). The pure fractions were combined andthe acetonitrile/TFA was removed in vacuo. The remaining aqueoussolution was made basic with NaHCO₃ and the free based product wasextracted into EtOAc. The organic phase was concentrated in vacuoyielding pure productN-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-chloropyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide(33.4 mg, 26.1% yield). ¹H NMR (CDCl3) 8.43 (d, 1H), 7.90 (s, 2H), 7.55(s, 1H), 7.38 (s, 1H), 6.68 (s, 1H), 5.49 (s, 2H), 3.66 (d, 8H) ppm.

Example 17N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-bromopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide

To a solution of potassium t-butoxide (0.070 g, 0.63 mmol) and t-butanol(0.5 mL) was added dropwise with stirring(2-bromo-pyridin-4-yl)-methanol (0.078 g, 0.42 mmol, prepared in thesimilar fashion as Example 16a from 2-Bromo-4-methyl-pyridine), followedby 4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (0.100 g, 0.21 mmol; prepared inExample 10b). The mixture was stirred at room temperature overnight.LC/MS analysis indicated formation of the desired product. The mixturewas concentrated in vacuo, and the crude product was purified onpreparative HPLC to affordN-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-bromopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide(13 mg, 10% yield). ¹H NMR (CDCl3) 8.40 (s, 1H), 7.95 (s, 2H), 7.45 (s,2H), 7.25 (m, 1H), 6.6 (s, 1H), 5.45 (m, 2H), 3.6 (m, 4H), 1.6 (m, 4H)ppm.

Example 18N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-bromopyridin-4-yl)methyl]-oxy}pyrazin-2-yl)piperazine-1-carboxamide

To a solution of potassium t-butoxide (0.073 g, 0.66 mmol) and t-butanol(0.5 mL) was added dropwise with stirring(2-bromo-pyridin-4-yl)-methanol (0.082 g, 0.44 mmol, prepared in thesimilar fashion as Example 16a from 2-Bromo-4-methyl-pyridine), followedby 3′-chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (0.100 g, 0.22 mmol; prepared inExample 16b). The mixture was stirred at room temperature overnight.LC/MS analysis indicated formation of the desired product. The mixturewas concentrated in vacuo, and the crude product was purified onpreparative HPLC to affordN-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-bromopyridin-4-yl)methyl]-oxy}pyrazin-2-yl)piperazine-1-carboxamide(5 mg). ¹H NMR (CDCl3) 8.40 (s, 1H), 7.95 (s, 2H), 7.8 (s, 1H), 7.6 (s,1H), 7.58 (m, 2H), 7.24 (m, 1H), 6.62 (s, 1H), 5.4 (s, 2H), 3.6 (m, 4H),1.6 (m, 4H) ppm.

Example 19N-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)-N′-[3-(trifluoromethyl)phenyl]urea

[1-(3-Chloro-pyrazin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butylester. To a round bottom flask equipped with a magnetic stir bar wasadded 2,3-Dichloro-pyrazine (3 g, 20.2 mmol) and dry DMF (50 mL).3-Boc-aminopyrrolidine (8.2 g, 44.5 mmol) was dissolved in dry DMF (50mL) and added to the round bottom flask. The reaction mixture wasallowed to continue to stir overnight at 100° C. LC/MS analysisindicated the desired product as the main component. The reactionmixture was cooled to room temperature and poured on ice. The mixturewas extracted with EtOAc and the EtOAc layer was washed with water andbrine and dried on sodium sulfate. After removal of solvent in vacuo thedesired product [1-(3-Chloro-pyrazin-2-yl)-pyrrolidin-3-yl]-carbamicacid tert-butyl ester (6.8 g, 99% yield) was obtained.

{1-[3-(Pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester. To a round-bottom flask purged with N₂ was chargedwith Potassium t-butoxide (7.6 g, 68.4 mmol) and t-butanol (140 mL). Themixture was flushed with N₂ for approximately 5 min., while stirring. Tothis mixture was added pyridylcarbinol (7.4 g, 68.4 mmol), followed by[1-(3-chloro-pyrazin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butylester (6.8 g, 22.8 mmol). The mixture was stirred at room temperatureovernight. The mixture was concentrated in vacuo, and then diluted withwater and extracted with EtOAc three times. The organic layer was washedwith water and brine, dried over sodium sulfate, and then concentratedin vacuo. Purification of the crude by column chromatography afforded{1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester (1 g, 12% yield).

1-[3-(Pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine. Tocompound{1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-yl}-carbamic acidtert-butyl ester (1 g, 2.6 mmole) was added 50% TFA/DCM. The mixture wasstirred for 1 hour, and concentrated in vacuo to give1-[3-(Pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine (1.2 g,100% yield).

N-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)-N′-[3-(trifluoro-methyl)phenyl]urea.To a solution of1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylamine (50 mg,0.18 mmole), triethylamine (excess eq.) in dichloromethane was added1-isocyanato-3-trifluoromethyl-benzene (37 mg, 0.198 mmole). The mixturewas stirred at room temperature for 1 hour. The mixture was thenconcentrated in vacuo, and purified by preparative HPLC to giveN-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)-N′-[3-(trifluoro-methyl)phenyl]urea(13.2 mg, 12.5% yield). ¹H NMR (DMSO-d6) 8.80 (m, 3H), 7.97 (s, 1H),7.90 (d, 2H), 7.68 (d, 1H), 7.4 (m, 2H), 7.3 (d, 1H), 7.2 (m, 1H), 6.8(d, 1H), 5.3 (s, 2H), 4.25 (m, H), 3.9 (m, 1H), 3.75 (m, 2H), 3.6 (m,1H), 2.40 (m, 1H), 1.85 (m, 1H) ppm.

Example 202-[2,5-bis(trifluoromethyl)phenyl]-N-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)acetamide

To a mixture of1-[3-(pyridin-4-ylmethoxy)-pyrazin-2-yl]-pyrrolidin-3-ylaminedihydrochloride (100 mg, 0.29 mmol, 1.0 eq.), triethyl amine (0.119 ml,0.858 mmol, 3.0 eq.), anhydrous DCM (1 mL), 2,5Bis(triflouoromethyl)phenyl acetic acid (116.7 mg, 0.429 mmol, 1.5 eq.),was added 1-Ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride(109.3 mg, 0.572 mmol, 2.0 eq.), followed by anhydrous1-Hydroxybenzotriazole (HOBT) (57.91 mg, 0.429 mmol, 1.5 eq.). Thereaction mixture was allowed to stir at room temperature overnight.After removal of solvent in vacuo, the mixture was purified onpreparative HPLC to give2-[2,5-bis(trifluoromethyl)phenyl]-N-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)acetamide(92.2 mg, 61% yield) as a white solid. ¹H NMR (CDCl₃) 8.58 (d, 2H),7.78-7.75 (s, 2H), 7.64 (d, 1H), 7.28-7.24 (m, 2H), 5.95 (d, 1H), 5.42(s, 2H), 4.58-4.54 (m, 1H), 3.90-3.87 (m, 1H), 3.79-3.67 (m, 4H),3.61-3.58 (m, 1H), 2.30-2.21 (m, 1H), 1.97-1.89 (m, 1H) ppm.

Example 21N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

4-{4-[(Pyridin-4-ylmethyl)-amino]-[1,2,5]thiadiazol-3-yl}-piperazine-1-carboxylicacid tert-butyl ester. To a round-bottom flask purged with N₂ wascharged with Pd (OAc)₂ (13.4 mg, 0.06 mmol, 2%), BINAP (37 mg, 0.02mmol, 2%), and dry toluene (15 mL), followed by addition of4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acidtert-butyl ester (912 mg, 3 mmol, prepared in Example 10b), picolylamine(388 mg, 3.6 mmol) and K2CO3 (2 g, 15 mmole). The mixture was refluxedwith vigorous stirring under N2 atmosphere until the desired product wasobserved (LC/MS analysis). The reaction mixture was cooled down to roomtemperature, filtered through a plug of celite. After removal of solventin vacuo, the crude reaction mixture was purified on preparative HPLC toobtain4-{4-[(pyridin-4-ylmethyl)-amino]-[1,2,5]thiadiazol-3-yl}-piperazine-1-carboxylicacid tert-butyl ester (25 mg).

N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide.To4-{4-[(pyridin-4-ylmethyl)-amino]-[1,2,5]thiadiazol-3-yl}-piperazine-1-carboxylicacid tert-butyl ester (25 mg) was added 50% TFA/DCM. After stirring atroom temperature for 1 hour, the mixture was concentrated in vacuo to adryness, giving the de-protected amine (33 mg). To this de-protectedamine (26 mg, 0.103 mmol) was added dichloromethane and triethylamine(excess eq.) with stirring, followed bis-trifluoromethylisocyanate (26.2mg, 0.103 mmole). The mixture was stirred at room temperature for 1hour. LC/MS analysis indicated the formation of desired product. Themixture was concentrated in vacuo and the crude product was purified onpreparative HPLC to giveN-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)amino]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide(14 mg). ¹H NMR (DMSO-d6) 9.41 (s, 1H), 8.65 (br, s, 2H), 8.2 (s, 2H),7.75 (d, 1H), 7.6 (s, 2H), 7.45 (t, 1H), 4.65 (d, 2H), 3.65 (m, 4H),3.22 (m, 4H) ppm.

Example 22N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(piperidin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide

4-(4-Chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol, prepared inExample 10b) was dissolved in 330 μL of t-butanol along with4-piperadine methanol (38 mg, 0.33 mmol). Then, 330 μL of 1.0 Mpotassium t-butoxide in t-butanol was added. The reaction mixture washeated to 50° C. overnight. The reaction was quenched with the additionof a few drops of trifluoroacetic acid and the solution was diluted to 2mL in volume with methanol. The reaction mixture was purified by reversephase HPLC to give 9 mg of the product as a white solid. ¹H NMR DMSO-d₆)δ 9.37 (s, 1H), 8.25 (s, 2H), 7.62 (s, 1H), 4.28 (d, 2H), 3.63 (m, 4H),3.54 (m, 4H), 3.08 (d, 2H), 2.59 (t, 2H), 1.93 (m, 1H), 1.71 (d, 2H),1.29 (qd, 2H) ppm.

Example 231-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine

4-(4-Chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine.3,4-Dichloro-1,2,5-thiadiazole (2.00 mL, 21.3 mmol) was dissolved in 70mL of t-butanol along with 4-pyridine methanol (1.05 g, 9.62 mmol). 30mL of 1.0 M potassium t-butoxide (30 mmol) was added and the reactionwas stirred at room temperature overnight. The reaction was diluted with100 mL of water and neutralized with 1.0 M HCl. The product wasextracted 3 times with 100 mL portions of ethyl acetate. The combinedorganic fractions were dried with magnesium sulfate and concentratedunder vacuum. The residue was purified by flash chromatography with a2:1 solution of hexanes in ethyl acetate, affording4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (821 mg) as anoff-white solid.

1-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine.4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine (50 mg, 0.22 mmol)was dissolved in 200 μL of DMF along with 1-phenylpiperazine (75 μL,0.49 mmol). The reaction was heated to 70° C. overnight. The reactionmixture was diluted with methanol to a volume of 2 mL and the reactionmixture was purified by reverse phase chromatography, affording1-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine(7 mg). ¹H NMR (DMSO-d₆) δ 8.62 (d, 2H), 7.46 (d, 2H), 7.23 (t, 2H),7.01 (d, 2H), 6.82 (t, 1H), 5.58 (s, 2H), 3.64 (m, 4H), 3.23 (m, 4H)ppm.

The following compounds were prepared in the similar fashion as Example23 from 4-(4-chloro-[1,2,5]thiadiazol-3-yloxymethyl)-pyridine:1-[(4-methylphenyl)methyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine.¹H NMR (DMSO-d₆) δ 8.57 (d, 2H), 7.41 (d, 2H), 7.19 (d, 2H), 7.11 (d,2H), 5.48 (s, 2H), 3.49 (m, 4H), 3.47 (s, 2H), 2.44 (m, 4H), 2.23 (s,3H) ppm.2-(4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazin-1-yl)pyrimidine.¹H NMR (DMSO-d6) 8.52 (s, 2H), 8.36 (s, 2H), 7.37 (s, 2H), 6.58 (s, 1H),5.47 (s, 2H), 3.80 (t, 4H), 3.51 (t, 4H) ppm.1-[2-nitro-4-(trifluoromethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine.¹H NMR (DMSO-d6) 8.57 (s, 2H), 8.17 (s, 1H), 7.86 (d, 1H), 7.53 (d, 1H),7.47-7.42 (m, 2H), 5.52 (s, 2H), 3.65-3.63 (t, 4H), 3.49-3.17 (t, 4H)ppm.1-[4-(4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazin-1-yl)phenyl]ethanone.¹H NMR (DMSO-d6) 8.87-8.57 (m, 2H), 7.90 (d, 2H), 7.79 (d, 2H), 6.96 (d,2H), 5.70 (s, 2H), 3.65-3.63 (m, 4H), 3.46-3.44 (m, 4H), 2.49 (s, 3H)ppm.

Example 24N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(2,3,5,6-tetrafluoropyridin-4-yl)amino]methyl}phenyl)piperazine-1-carboxamide

4-(2-Cyanophenyl)piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide. 1-(2-Cyanophenyl)piperazine (1.0g, 5.34 mmol) was dissolved in 25 mL of dichloromethane. Then,triethylamine (820 μL, 5.88 mmol) was added, followed by3,5-bis(trifluoromethyl)phenyl isocyanate (1020 μL, 5.87 mmol). Thereaction stirred at room temperature overnight. The reaction mixture wasdiluted with 50 mL of water and extracted three times with 25 mLportions of ethyl acetate. The combined organic fractions were washedtwice with 25 mL of 0.1 M HCl, once with 25 mL of water, and once with25 mL of saturated sodium bicarbonate. The organic fraction was driedwith magnesium sulfate and concentrated under vacuum. The crude productwas used without further purification.

4-(2-Aminomethylphenyl)piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)amide.4-(2-Cyanophenyl)piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (˜5.3 mmol) was dissolved in 50mL of ethanol. 5 mL of aqueous NH₄OH was added along with 500 mg of 50%Raney nickel in water. The reaction mixture was hydrogenated in a Parrshaker at 45 psi overnight. The reaction mixture was filtered through aplug of Celite and concentrated under vacuum. 2.5 g of crude product wasobtained, and used without further purification.

N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(2,3,5,6-tetrafluoropyridin-4-yl)amino]methyl}phenyl)piperazine-1-carboxamide.4-(2-Aminomethyl-phenyl)piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol) was dissolvedin 500 mL of acetonitrile. Then, triethylamine (20 L, 0.14 mmol) wasadded, followed by pentafluoropyridine (16 μL, 0.15 mmol). The reactionwas stirred at room temperature overnight. The reaction mixture wasdiluted to 2 mL in volume with methanol and the mixture was purified byreverse phase HPLC to give 44 mg of the product as a white solid. ¹H NMR(CDCl₃) δ 7.87 (s, 2H), 7.51 (s, 1H), 7.29-7.36 (m, 2H), 7.16-7.21 (m,2H), 6.78 (s, 1H), 5.90 (br s, 1H), 4.79 (d, 2H), 3.71 (m, 4H), 3.02 (t,4H) ppm.

Example 25N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(3-chloro-2,5,6-trifluoropyridin-4-yl)amino]methyl}phenyl)piperazine-1-carboxamide

4-(2-Aminomethyl-phenyl)piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)amide (50 mg, 0.11 mmol, prepared inExample 26b) was dissolved in 500 μL of acetonitrile. Then,triethylamine (20 μL, 0.14 mmol) was added, followed by3-chloro-2,4,5,6-tetrafluoropyridine (17 μL, 0.15 mmol). The reactionwas stirred at room temperature overnight. The reaction mixture wasdiluted to 2 mL in volume with methanol and the mixture was purified byreverse phase HPLC to give 15 mg of the product as a white solid. ¹H NMR(CDCl₃) δ 7.88 (s, 2H), 7.52 (s, 1H), 7.31-7.38 (m, 2H), 7.15-7.22 (m,2H), 6.70 (s, 1H), 5.88 (br t, 1H), 4.85 (dd, 2H), 3.71 (m, 4H), 3.02(t, 4H) ppm.

Example 26N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide

3′-Pyridin-4-ylethynyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid (3,5-bis-trifluoromethylphenyl)amide.3′-Chloro-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid(3,5-bis-trifluoromethylphenyl)amide (200 mg, 0.441 mmol, prepared inExample 16b) was dissolved in 1.8 mL of acetonitrile. Another mixturewas prepared containing 4-ethynylpyridine hydrochloride (125 mg, 0.896mmol), palladium(II) acetate (12 mg, 0.053 mmol), copper(I) iodide (5mg, 0.026 mmol), triphenylphosphine (28 mg, 0.107 mmol) andtriethylamine (600 μL) in 600 μL of acetonitrile. The two mixtures werecombined and stirred at 80° C. for 1 hr under a nitrogen atmosphere. Thereaction mixture was filtered through Celite and concentrated undervacuum. The material was used without further purification.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide.3′-Pyridin-4-ylethynyl-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylicacid (3,5-bis-trifluoromethylphenyl)amide (˜0.4 mmol) was dissolved in 5mL ethanol. Then, 50 mg of 10% palladium on carbon was added. Thereaction flask was flushed with hydrogen and the reaction was stirred atroom temperature for 5 hr under 1 atmosphere of hydrogen. The reactionmixture was filtered through Celite and concentrated under vacuum. Theresidue was purified by reverse phase HPLC to giveN-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide(80 mg) as a yellow solid. ¹H NMR (DMSO-d₆) δ 9.34 (s, 1H), 8.48 (d,2H), 8.23 (s, 1H), 8.20 (d, 1H), 8.14 (d, 2H), 7.58 (s, 1H), 7.39 (d,2H), 3.66 (m, 4H), 3.13-3.43 (m, 8H) ppm.

Example 27N-[3,5-Bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide

2-Chloro-3-(pyridin-4-ylmethoxy)pyridine. 2-Chloro-3-pyridinol (500 mg,3.86 mmol) was dissolved in 20 mL of tetrahydrofuran along with4-pyridyl methanol (465 mg, 4.26 mmol) and triphenylphosphine (1.15 g,4.38 mmol). To this solution was added diisopropylazodicarboxylate (840μL, 4.27 mmol). The reaction was stirred at room temperature overnightunder a nitrogen atmosphere. The solvent was removed under vacuum andthe residue was dissolved in 50 mL of ethyl acetate. The reactionmixture was washed 4 times with 25 mL portions of water. Then, theproduct was extracted by washing 3 times with 25 mL portions of 0.5 MHCl. The acidic washes were neutralized with 1.0 M NaOH and the productwas extracted back into ethyl acetate with 3 washes of 25 mL. Thecombined organic fractions were dried with magnesium sulfate andconcentrated under vacuum to give 620 mg of2-chloro-3-(pyridin-4-ylmethoxy)pyridine as a yellow solid.

4-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]piperazine-1-carboxylic acidtert-butyl ester. 2-Chloro-3-(pyridin-4-ylmethoxy)pyridine (620 mg, 2.81mmol) was dissolved in 3 mL DMF along with Boc-piperazine (2.5 g, 13.4mmol). The reaction mixture was stirred at 140° C. for 48 hr. Thereaction mixture solidified upon cooling and the product was extractedfrom the solid material by washing with a solution of ethyl acetate inhexanes (1:2). The organic washes were concentrated to give about 500 mgof the amine adduct in 50% purity, which was used for the next reactionwithout purification.

1-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]-piperazine trifluoroacetic acidsalt. The crude4-[3-(Pyridin-4-ylmethoxy)-pyridin-2-yl]piperazine-1-carboxylic acidtert-butyl ester (˜500 mg) was dissolved in 10 mL of 30% trifluoroaceticacid in dichloromethane. The reaction mixture was stirred for 3 hr andthen the solvent was removed under vacuum. The impure material was usedwithout purification.

N-[3,5-Bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide.The crude 1-[3-(Pyridin-4-ylmethoxy)pyridin-2-yl]-piperazinetrifluoroacetic acid salt (˜500 mg) was dissolved in 25 mL oftetrahydrofuran along with 2 g of trisamine resin. The suspension wasstirred for 1 hr and the resin was removed by filtration. The filtratewas concentrated under vacuum. The free-based material was dissolved in5 mL of dichloromethane. To this solution was added triethylamine (150μL, 1.08 mmol) and 3,5-bis(trifluoromethyl)phenyl isocyanate (150 μL,0.864 mmol). The reaction was stirred at room temperature for 1 hr. Thereaction mixture was concentrated under vacuum and re-dissolved in 25 mLethyl acetate. The reaction mixture was washed 3 times each with 25 mLportions of water, 0.05 M HCl and saturated aqueous sodium chloride. Theorganic fraction was dried with magnesium sulfate and concentrated undervacuum. The residue was purified by flash chromatography with a gradientof 0% to 10% methanol in ethyl acetate with 5% triethylamine, givingN-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide(14 mg). ¹H NMR (DMSO-d₆) δ 9.24 (s, 1H), 8.60 (d, 2H), 8.22 (s, 2H),7.84 (d, 1H), 7.58 (s, 1H), 7.46 (d, 2H), 7.33 (d, 1H), 6.92 (dd, 1H),5.23 (s, 2H), 3.62-3.68 (m, 4H) 3.37-3.41 (m, 4H) ppm.

Example 28N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-yloxy)methyl]phenyl}piperazine-1-carboxamide

2-piperazin-1-yl-benzoic acid sulfuric acid salt.1-(2-Cyanophenyl)piperazine (2.00 g, 10.68 mmol) was suspended in 10 mLof concentrated sulfuric acid. The piperazine slowly dissolved as thereaction mixture was heated to 100° C. After heating the reaction for 2hr, the reaction was cooled to room temperature. 10 mL of water wasadded and the reaction was heated to 100° C. for another 4 hr. Aftercooling to room temperature, the reaction mixture was poured into 200 mLof ice water. The aqueous mixture was neutralized with ammoniumhydroxide and the mixture was concentrated under vacuum. The product wasextracted from the inorganic salts by washing with 25% methanol intetrahydrofuran. The crude material was used in the next step withoutpurification.

(2-piperazin-1-yl-phenyl)-methanol. 2-piperazin-1-yl-benzoic acidsulfuric acid salt (˜10 mmol) was suspended in 50 mL of tetrahydrofuran.Then 100 mL of 1.0 M borane in tetrahydrofuran (100 mmol) was added andthe reaction was stirred at room temperature overnight with a bubblerattached to release pressure in the flask. The reaction mixture wasdiluted with 50 mL of methanol. The reduced product (470 mg)crystallized out of the mixture during evaporation.

1-[2-(Pyridin-4-yloxymethyl)phenyl]piperazine.(2-piperazin-1-yl-phenyl)-methanol (200 mg, 1.04 mmol) was added to asuspension of 4-chloropyridine hydrochloride (225 mg, 1.50 mmol),tris[2-(2-methoxy)ethyl]amine (32 μL, 0.10 mmol), powdered potassiumhydroxide (225 mg, 4.01 mmol) and potassium carbonate (275 mg, 1.99mmol) in 10 mL of toluene. The reaction mixture was heated to 120° C.overnight. The reaction mixture was concentrated and the residue waspurified by reverse phase HPLC. The material was still less than 50%pure, but was used in the next step without further purification.

N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4-yloxy)methyl]phenyl}-piperazine-1-carboxamide.The impure 1-[2-(Pyridin-4-yloxymethyl)phenyl]piperazine (˜50 mg) wasdissolved in 5 mL of dichloromethane along with triethylamine (50 μL,0.36 mmol). 3,5-Bis(trifluoromethyl)phenyl isocyanate (50 μL, 0.29 mmol)was added and the reaction was stirred at room temperature overnight.The solvent was removed under vacuum and the residue was dissolved in 2mL methanol. The reaction mixture was purified by reverse phase HPLC togive 10 mg of product as a white solid. ¹H NMR (DMSO-d₆) δ 10.58 (s,1H), 8.28 (d, 2H), 8.17 (s, 2H), 7.73 (s, 1H), 7.49 (d, 1H), 7.38 (t,1H), 7.18-7.25 (m, 4H), 5.39 (s, 2H), 3.80-3.85 (m, 4H) 3.00-3.04 (m,4H).

Example 29(4-{4-[4-(3,5-Bis-trifluoromethyl-phenylcarbamoyl)-piperazin-1-yl]-[1,2,5]thiadiazol-3-yloxymethyl-pyridin-2-yl)-carbamicacid tert-butyl ester

(4-Hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester. Asolution of (2-fluoro-pyridin-4-yl)-methanol (450 mg, 3.54 mmol) in 28%aqueous ammonia (5 mL) was heated in a sealed pressure tube at 150° C.for 17 h and at 175° C. for 21 h. The cooled solution was evaporated toa residue, which was partitioned between 1M K₂CO₃ and ethyl acetate. Theaqueous phase was saturated with NaCl and extracted with severalportions of ethyl acetate. The combined organic extracts were dried(Na₂SO₄), filtered and evaporated. The crude residue was dissolved int-BuOH (5 mL) and was treated with di-tert-butyl dicarbonate (405 mg,1.85 mmol) and stirred at room temperature for 15 h. The solvent wasevaporated, and the crude residue was chromatographed on silica gel(1/1-CH₂Cl₂/ethyl acetate) to afford(4-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (196 mg,25%) as a solid: ¹H NMR (400 MHz, CDCl₃) δ 1.53 (s, 9H), 2.27 (br s,1H), 4.72 (s, 2H), 6.98 (m, 1H), 7.93 (s, 1H), 8.24 (d, 1H, J=5.2), 8.65(s, 1H).

4-[4-(2-Amino-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide. To a solution of(4-hydroxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester (100 mg,0.45 mmol) and4-(4-chloro-[1,2,5]thiadiazol-3-yl)-piperazine-1-carboxylic acid(3,5-bis-trifluoromethyl-phenyl)-amide (207 mg, 0.45 mmol) in t-BuOH (5mL) was added solid potassium tert-butoxide (200 mg, 1.8 mmol) in oneportion. The reaction solution was stirred at room temperature for 2 hand then at 40° C. for 1.75 h. Excess base was quenched with severaldrops of acetic acid and the volatiles were evaporated. The residue waspartitioned between ethyl acetate and saturated NaHCO₃. The organicphase was washed with saturated NaCl, dried (MgSO₄), filtered andevaporated. Chromatography on silica gel (2/1-hexane/ethyl acetate)afforded a solid material that was recrystallized (hexane/ethyl acetate)to give(4-{4-[4-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-piperazin-1-yl]-[1,2,5]thiadiazol-3-yloxymethyl-pyridin-2-yl)-carbamicacid tert-butyl ester (89 mg, 30%) as a crystalline adduct (1.3:1) withethyl acetate: ¹H NMR (400 MHz, CDCl₃) δ 1.52 (s, 9H), 3.71 (m, 8H),5.49 (s, 2H), 6.77 (s, 1H), 6.96 (m, 1H), 7.53 (s, 1H), 7.89 (s, 2H),7.93 (s, 1H), 8.12 (s, 1H), 8.27 (d, 1H, J=4.8); MS: 648 (M+1).

Example 304-[4-(2-Amino-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide trifluoroacetate

A solution of(4-{4-[4-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-piperazin-1-yl]-[1,2,5]thiadiazol-3-yloxymethyl-pyridin-2-yl)-carbamicacid tert-butyl ester (40 mg, 0.062 mmol) in CH₂Cl₂ (1.5 mL) was treatedwith trifluoroacetic acid (1.5 mL), stirred at room temperature for 2.5h and then was evaporated. The residue was dissolved inacetonitrile/water, filtered and lyophilized to afford4-[4-(2-Amino-pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylicacid (3,5-bis-trifluoromethyl-phenyl)-amide trifluoroacetate (38 mg,93%) as a white solid: ¹H NMR (400 MHz, CD₃OD) δ 3.64 (m, 4H), 3.71 (m,4H), 5.58 (s, 2H), 6.92 (dd, 1H, J=2, 6.4), 7.54 (s, 1H), 7.84 (dd, 1H,J=0.8, 6.8), 8.08 (s, 1H); MS: 548 (M+1).

Example 31(4-{4-[4-(3,5-Bis-trifluoromethyl-phenylcarbamoyl)-piperazin-1-yl]-[1,2,5]thiadiazol-3-yloxymethyl}-pyridin-2-yl)-carbamicacid methyl ester

A solution of(4-{4-[4-(3,5-bis-trifluoromethyl-phenylcarbamoyl)-piperazin-1-yl]-[1,2,5]thiadiazol-3-yloxymethyl-pyridin-2-yl)-carbamicacid tert-butyl ester (45 mg, 0.070 mmol) in CH₂Cl₂ (3 mL) was treatedwith trifluoroacetic acid (3 mL), stirred at rt for 1 h and then wasevaporated. The residue was dissolved in CH₂Cl₂ (3 mL) and was treatedwith iPr₂NEt (36 μL, 0.31 mmol) and methyl chloroformate (6 μL, 0.08mmol). After stirring for 1 h at room temperature, a second portion ofmethyl chloroformate (3 μL) was added and the reaction was stirred for 1h more. The solvent was evaporated, and the residue was partitionedbetween ethyl acetate and saturated NaHCO₃. The organic phase was washedwith saturated NaCl, dried (MgSO₄), filtered and evaporated.Chromatography on silica gel (5/1-CH₂Cl₂/ethyl acetate) afforded asolid, which was dissolved in ethyl acetate and precipitated withhexane. The supernatant was removed and the solid was dissolved indioxane, filtered and lyophilized to afford(4-{4-[4-(3,5-Bis-trifluoromethyl-phenylcarbamoyl)-piperazin-1-yl]-[1,2,5]thiadiazol-3-yloxymethyl}-pyridin-2-yl)-carbamicacid methyl ester (6.5 mg, 15%) as a white solid: ¹H NMR (400 M&,DMSO-d₆) δ 3.58-3.67 (m overlapping s, 11H), 5.54 (s, 2H), 7.10 (d, 1H,J=5.2), 7.62 (s, 1H), 7.98 (s, 1H), 8.22 (s, 2H), 8.28 (d, 1H, J=5.2),9.30 (s, 1H), 10.31 (s, 1H); MS: 606 (M+1).

EXEMPLARY EMBODIMENTS

The following compounds listed in Table 2 are examples in accordancewith formula I. Generally, the compounds listed in Table 2 wereidentified by LC-MS, isolated, and characterized by ¹H-NMR (mosttypically 400 MHz). Liquid chromatography-mass spectral (LC-MS) analyseswere performed using at least one of: a Hewlett-Packard Series 1100 MSD,an Agilent 1100 Series LC/MSD (available from Agilent TechnologiesDeutschland GmbH of Waldbronn Germany), or a Waters 8-Channel MUX System(available from Waters Corporation of Milford, Mass.).

Compounds were identified according to either their observed mass [M+1]ion (positive mode) or [M−1] ion (negative mode). Three LC-MSconditions, and methods used, are as follows: Method A: Agilent, method3.3_(—)1 ml; Column: C18, 30×3 mm, 5 micron; (BP Series 1100 MSD);Solvent: A 0.05 M NH4OAc/Water. B Acetonitrile; Flow rate: 1 ml/min;Gradient: 0-0.25 min, 20% B, 0.25-1.25 min, 20-90% B, 1.25-2 min, 90% B;Total run time: 3 min; UV: 220 and 254 nm. Method B: Agilent, method3×3ACCN; Column: C18, 30×4.6 mm, 3.5 micron; (Agilent 1100 SeriesLC/MSD); Flow rate: 2 ml/min; UV: 254 nm; Solvent and Gradient are thesame as for method A. Method C: Waters, method 220POS: Column: WatersXterra C18, 15×2.0 mm; (Waters 8-Channel MUX System); Solvent: A=0.01%TFA in H2O; B=0.01% TFA in MeOH; Flow rate: 3.5 mL/min; Gradient: 0-0.20min, 5% B; 0.20-2.75 min, 5-100% B; 2.75-3.25 min, 100% B; 3.25-3.30min, 100-5% B; 3.30-3.50 min, 5% B; Total run time: 3.5 min; UV: 220 nm.

¹H-NMR data for compounds was taken with a Varian AS400 Spectrometer(400 MHz, available from Varian GmbH, Darmstadt, Germany).

TABLE 2 Calculated Retention Parent Observed Time # Name MW Mass (min)Method ¹H-NMR 1 N-[(1R,2S)-2- 436.54 437.2 1.71 B (CD₃OD) 8.69(d, 2H),7.87(d, phenylcyclopropyl]-4-{4- 2H), 7.13(m, 2H), 7.03(m, 3H),[(pyridin-4-ylmethyl)oxy]- 5.68(s, 2H), 3.45(m, 8H), 1,2,5-thiadiazol-3-2.66(m, 1H), 1.91(m, 1H), 1.07(m, yl}piperazine-1- 2H) ppm carboxamide 2N-[3,5- 532.47 533.1 1.89 B (CDCl3) 8.62(d, 2H), 7.84(s, 2H),bis(trifluoromethyl)phenyl]- 7.50(s, 1H), 7.31(d, 2H), 7.06(s,4-{4-[(pyridin-4- 1H), 5.49(s, 2H), 3.68-3.60(m, ylmethyl)oxy]-1,2,5-8H) ppm thiadiazol-3-yl}piperazine- 1-carboxamide 3 N-[3,5- 532.47 5331.83 A (DMSO-d6) 9.29(s, 1H), 8.62(d, bis(trifluoromethyl)phenyl]- 2H),8.23(s, 2H), 7.65(s, 1H), 4-{4-[(pyridin-4- 7.45(d, 2H), 5.68(s, 2H),3.69(m, ylmethyl)oxy]-1,2,5- 4H), 3.58(m, 4H) ppmthiadiazol-3-yl}piperazine- 1-carboxamide 4 N-[4-(1- 438.55 439 1.82 B(CDCl3) 8.638-8.622(d, 2H), methylethyl)phenyl]-4-{4- 7.311-7.296(d,2H), [(pyridin-4-ylmethyl)oxy]- 7.248-7.227(d, 2H), 7.152-7.131(d, 2H),1,2,5-thiadiazol-3- 6.284(br. s, 1H), 5.480(s, 2H), 3.615(s,yl}piperazine-1- 8H), 2.89-2.82(m, 1H), carboxamide 1.231-1.214(d, 6H)ppm 5 N-(3-bromophenyl)-4-{4- 475.37 476 2.11 C[(pyridin-4-ylmethyl)oxy]- 1,2,5-thiadiazol-3- yl}piperazine-1-carboxamide 6 N-[3-(methylthio)phenyl]- 442.57 443.0 1.65 B (CDCl₃)8.63(d, 2H), 7.32(m, 4-{4-[(pyridin-4- 3H), 7.18(m, 1H), 7.07(m, 1H),ylmethyl)oxy]-1,2,5- 6.98(m, 1H), 6.48(br. s, 1H),thiadiazol-3-yl}piperazine- 5.48(s, 2H), 3.62(m, 8H), 2.47(s, 3H)1-carboxamide ppm 7 N-(3-ethylphenyl)-4-{4- 424.53 425.1 1.66 B (CDCl₃)8.68(br. s, 2H), 7.50(d, [(pyridin-4-ylmethyl)oxy]- 2H), 7.16(m, 2H),6.87(d, 1H), 1,2,5-thiadiazol-3- 6.57(s, 1H), 5.55(s, 2H), 3.63(m,yl}piperazine-1- 8H), 2.61(q, 2H), 1.22(t, 3H) ppm carboxamide 8N-(3,5-dimethylphenyl)-4- 424.53 425 1.95 C {4-[(pyridin-4-ylmethyl)oxy]-1,2,5- thiadiazol-3-yl}piperazine- 1-carboxamide 94-{4-[(pyridin-4- 464.47 465.1 1.74 B (CDCl₃) 8.63(d, 2H), 7.63(s, 1H),ylmethyl)oxy]-1,2,5- 7.55(d, 1H), 7.38(m, 1H), thiadiazol-3-yl}-N-[3-7.32(m, 3H), 6.60(s, 1H), 5.48(s, 2H),(trifluoromethyl)phenyl]piperazine- 3.63(m, 8H) ppm 1-carboxamide 10N-[3,5- 596.55 597.1 2.05 A (DMSO-d6) 9.31(s, 1H), 8.33(d,bis(trifluoromethyl)phenyl]- 1H), 8.21(s, 2H), 8.14(d, 1H),4-(4-{[(2-methylquinolin- 8.01(t, 1H), 7.85(t, 1H), 7.80(s,4-yl)methyl]oxy}-1,2,5- 1H), 7.61(s, 1H), 6.14(s, 2H),thiadiazol-3-yl)piperazine- 3.61(m, 4H), 3.56(m, 4H), 1-carboxamide2.85(s, 3H) ppm 11 N-[3,5- 574.55 573.1 2.21 A (DMSO-d6) 9.23(s, 1H),8.18(s, bis(trifluoromethyl)phenyl]- 2H), 7.59(s, 1H), 7.22(m, 1H),4-[4-({[3- 6.89(s, 1H), 6.78(m, 2H), (dimethylamino)phenyl]methyl}5.39(m, 4H), 3.61(m, 4H), 3.53(m, oxy)-1,2,5-thiadiazol- 4H), 2.92(s,6H) ppm 3-yl]piperazine-1- carboxamide 12 N-[3,5- 556.49 555.1 1.95 A(DMSO-d6) 9.17(s, 1H), 9.09(s, bis(trifluoromethyl)phenyl]- 1H), 8.15(s,2H), 7.81(d, 1H), 4-[4-(1H-indol-5-yloxy)- 7.53(m, 2H), 6.96(d, 1H),6.75(d, 1,2,5-thiadiazol-3- 1H), 6.63(d, 1H), 3.53(m, 4H),yl]piperazine-1- 3.02(m, 4H) ppm carboxamide 13 N-[3,5- 537.51 536.12.08 A (CDCl3) 7.88(s, 2H), 7.53(s, bis(trifluoromethyl)phenyl]- 1H),7.40-7.39(m, 1H), 7.36(dd, 4-{4-[(3- 1H), 7.17(dd, 1H), 6.67(s, 1H),thienylmethyl)oxy]-1,2,5- 5.48(s, 2H), 3.64-3.61(m, 8H)thiadiazol-3-yl}piperazine- ppm 1-carboxamide 14 N-[3,5- 554.51 553.11.87 A (DMSO-d6) 9.36(s, 1H), 8.22(s, bis(trifluoromethyl)phenyl]- 2H),7.62(s, 1H), 4.74(m, 2H), 4-{4-[(2-morpholin-4- 4.00(bs, 2H), 3.58(m,15H), ylethyl)oxy]-1,2,5- 3.23(bs, 2H) ppm thiadiazol-3-yl}piperazine-1-carboxamide 15 N-[3,5- 535.47 534.1 1.81 A (DMSO-d6) 9.32(s, 1H),8.22(s, bis(trifluoromethyl)phenyl]- 2H), 7.71(d, 1H), 7.62(d, 1H),4-(4-{[2-(1H-imidazol-1- 7.27(s, 1H), 6.93(s, 1H), 4.65(m,yl)ethyl]oxy}-1,2,5- 2H), 4.44(m, 2H), 3.56(m, 4H),thiadiazol-3-yl)piperazine- 3.39(m, 4H) ppm 1-carboxamide 16 N-[3,5-538.52 537.2 1.68 A (DMSO-d6) 9.31(s, 1H), 8.23(s,bis(trifluoromethyl)phenyl]- 2H), 7.63(s, 1H), 3.63(m, 4H),4-{4-[(1-methylpiperidin- 3.58(m, 4H), 3.34(m, 8H),4-yl)oxy]-1,2,5-thiadiazol- 2.80(m, 3H) ppm 3-yl}piperazine-1-carboxamide 17 N-[3,5- 561.51 560.1 2.1 B (DMSO-d6) 9.22(s, 1H), 8.17(s,bis(trifluoromethyl)phenyl]- 2H), 7.59(s, 1H), 7.42(d, 2H), 4-[4-({[4-6.95(d, 2H), 5.37(s, 2H), 3.75(s, (methyloxy)phenyl]methyl} 3H), 3.56(t,4H), 3.48(t, 4H) ppm oxy)-1,2,5-thiadiazol-3- yl]piperazine-1-carboxamide 18 4-[4-({[3,4- 591.53 590.1 2.05 B (DMSO-d6) 9.24(s, 1H),8.20(s, bis(methyloxy)phenyl]methyl} 2H), 7.61(s, 1H), 7.12(s, 1H),oxy)-1,2,5-thiadiazol- 7.04(d, 1H), 7.00(d, 1H), 5.38(s, 3-yl]-N-[3,5-2H), 3.80-3.76(m, 8H), bis(trifluoromethyl)phenyl] 3.59-3.51(m, 6H) ppmpiperazine-1-carboxamide 19 4-{4-[(1,3-benzodioxol-5- 575.49 574.1 2.08B (DMSO-d6) 9.24(s, 1H), 8.21(s, ylmethyl)oxy]-1,2,5- 2H), 7.61(s, 1H),7.10(s, 1H), thiadiazol-3-yl}-N-[3,5- 7.01(d, 1H), 6.96(d, 1H), 6.04(s,bis(trifluoromethyl)phenyl] 2H), 5.35(s, 2H), 3.59(t, 4H),piperazine-1-carboxamide 3.51(t, 4H) ppm 20 N-[3,5- 521.44 520.1 2.04 B(DMSO-d6) 9.28(s, 1H), 8.23(s, bis(trifluoromethyl)phenyl]- 2H), 7.89(s,1H), 7.72(s, 1H), 4-{4-[(furan-3- 7.65(d, 1H), 6.67(d, 1H), 5.36(s,ylmethyl)oxy]-1,2,5- 2H), 3.65(t, 4H), 3.56(t, 4H) ppmthiadiazol-3-yl}piperazine- 1-carboxamide 21 N-[3,5- 525.47 524.1 1.98 B(DMSO-d6) 9.26(s, 1H), 8.20(s, bis(trifluoromethyl)phenyl]- 2H), 7.59(s,1H), 4.37-4.27(m, 4-{4-[(tetrahydrofuran-3- 2H), 3.79-3.73(m, 2H),ylmethyl)oxy]-1,2,5- 3.67-3.50(m, 10H), 2.72-2.69(m, 1H),thiadiazol-3-yl}piperazine- 2.03-2.00(m, 1H), 1.68-1.64(m, 1H)1-carboxamide ppm 22 N-[3,5- 546.49 547.1 1.96 B (CDCl3) 8.80(br., d,2H), 7.93(s, bis(trifluoromethyl)phenyl]- 2H), 7.66(d, 2H), 7.53(s, 1H),2-methyl-4-{4-[(pyridin- 6.90(s, 1H), 5.64(d, 2H),4-ylmethyl)oxy]-1,2,5- 4.43(br., m, 1H), 4.17(d, 1H), 4.07(d,thiadiazol-3-yl}piperazine- 1H), 3.98(d, 1H), 3.46(td, 1H),1-carboxamide 3.20(dd, 1H), 3.11(td, 1H) 1.39(d, 3H) ppm 23 N-[3,5-546.49 547 1.84 B (CDCl3) 9.52(s, 2H), 7.838(s,bis(trifluoromethyl)phenyl]- 2H), 7.508(s, 1H), 7.321-7.307(d,4-{4-[(pyridin-4- 2H), 6.769(br. s, 1H), 5.464(s, ylmethyl)oxy]-1,2,5-2H), 3.925-3.851(m, 4H), thiadiazol-3-yl}-1,4- 3.820-3.790(t, 2H),3.612-3.582(t, 2H), diazepane-1-carboxamide 1.987-1.959(m, 2H) ppm 241-({[(1S,2R,5S)-5-methyl- 473.64 474.2 2.14 B (CD₃OD) 8.83(d, 2H),8.04(d, 2-(1- 2H), 5.81(s, 2H), 4.33(d, 1H), methylethyl)cyclohexyl]oxy}4.16(d, 1H), 3.75-3.56(m, 8H), acetyl)-4-{4-[(pyridin-4- 3.23(m, 1H),2.19(m, 2H), 1.66(m, ylmethyl)oxy]-1,2,5- 2H), 1.37(m, 1H), 1.26(m, 1H),thiadiazol-3-yl}piperazine 1.05(m, 1H), 1.02-0.82(m, 8H), 0.79(d, 3H)ppm 25 5-phenyl-N-(1-{4- 448.51 449 1.76 B (CDCl3) 8.629-8.614(d, 2H),[(pyridin-4-ylmethyl)oxy]- 8.304-8.279(m, 2H), 7.842(s, 1H),1,2,5-thiadiazol-3- 7.506-7.395(m, 4H), yl}pyrrolidin-3-yl)-1,3-7.333-7.318(d, 2H), 5.460(s, 2H), 4.739(m, oxazole-4-carboxamide 1H),4.062-4.019(m, 1H), 3.899-3.755(m, 3H), 2.40-2.31(m, 1H), 2.13-2.08(m,1H) ppm 26 1-{4-[(pyridin-4- 463.48 464.1 1.81 B (CD₃OD) 8.83(d, 2H),8.05(d, ylmethyl)oxy]-1,2,5- 2H), 7.60-7.54(m, 4H), 5.81(s,thiadiazol-3-yl}-4-{[3- 2H), 3.94(s, 2H), 3.74(m, 4H),(trifluoromethyl)phenyl]acetyl} 3.57(m, 2H), 3.52(m, 2H) ppm piperazine27 N-[3,5- 538.52 539.2 1.69 B (DMSO-d₆) δ 9.37(s, 1H), 8.25(s,bis(trifluoromethyl)phenyl]- 2H), 7.62(s, 1H), 4.28(d, 2H),4-{4-[(piperidin-4- 3.63(m, 4H), 3.54(m, 4H), ylmethyl)oxy]-1,2,5-3.08(d, 2H), 2.59(t, 2H), 1.93(m, 1H), thiadiazol-3-yl}piperazine-1.71(d, 2H), 1.29(qd, 2H) 1-carboxamide 28 N-[3,5- 561.51 561 1.85 B(DMSO-d6) 9.207(s, 1H), bis(trifluoromethyl)phenyl]- 8.607-8.593(d, 2H),8.083,(s, 2H), N′-[(1-{4-[(pyridin-4- 7.55(s, 1H), 7.438-7.423(d, 2H),ylmethyl)oxy]-1,2,5- 6.621-6.592(t, 1H), 5.520(s, 2H),thiadiazol-3-yl}piperidin- 4.163-4.131(d, 2H), 4-yl)methyl]urea3.302-3.031(t, 2H), 2.909-2.850(t, 2H), 1.743-1.713(m, 3H),1.274-1.243(m, 2H) ppm 29 N-[3,5- 560.52 561.1 1.98 B (DMSO-d6) 9.30(s,1H), 8.70(s, bis(trifluoromethyl)phenyl]- 2H), 8.23-8.19(m, 3H),4-{4-[(3-pyridin-3- 7.79-7.75(m, 1H), 7.59(s, 1H), ylpropyl)oxy]-1,2,5-4.44-4.40(m, 2H), 3.61(t, 4H), 3.48(t, 4H), thiadiazol-3-yl}piperazine-2.91-2.87(m, 2H), 2.18-2.14(m, 1-carboxamide 2H) ppm 30 N-[3,5- 564.47563 1.55 A (DMSO-d6) 9.25(s, 1H), 8.29(d, bis(trifluoromethyl)phenyl]-2H), 8.21(s, 2H), 7.62(s, 1H), 4-{1,1-dioxido-4- 7.56(d, 2H), 5.46(d,2H), 3.65(m, [(pyridin-4-ylmethyl)oxy]- 8H) ppm 1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide 31 4-[4-(1- 550.53 549 1.52 A (DMSO-d6)9.81(s, 1H), 9.31(s, azabicyclo[2.2.2]oct-3- 1H), 8.21(s, 2H), 7.60(s,1H), yloxy)-1,2,5-thiadiazol-3- 5.20(m, 1H), 3.80-3.21(m, 15H),yl]-N-[3,5- 2.00-1.75(m, 4H) ppm bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 32 4-[({4-[4-({[3,5- 575.49 574 1.62 A(DMSO-d6) 9.24(s, 1H), 8.19(s, bis(trifluoromethyl)phenyl] 2H), 7.96(d,2H), 7.59(s, 2H), amino}carbonyl)piperazin- 7.57(s, 1H), 5.54(s, 2H),1-yl]-1,2,5-thiadiazol-3- 3.62-3.52(m, 8H) ppm yl}oxy)methyl]benzoicacid 33 N-[3,5- 538.52 537 1.5 A (DMSO-d6) 9.30(s, 1H), 8.20(s,bis(trifluoromethyl)phenyl]- 2H), 7.60(s, 1H), 4.32(m, 2H),4-{4-[(piperidin-3- 3.63-3.51(m, 8H), 1.99(m, 7H), ylmethyl)oxy]-1,2,5-1.82(m, 2H) ppm thiadiazol-3-yl}piperazine- 1-carboxamide 34 N-[3,5-538.52 537 1.54 A (DMSO-d6) 9.90(br., s, 1H),bis(trifluoromethyl)phenyl]- 9.33(s, 1H), 8.20(s, 2H), 7.60(s, 1H),4-{4-[(2-pyrrolidin-1- 4.70(t, 2H), 3.70-3.34(br., m,ylethyl)oxy]-1,2,5- 12H), 3.13(br., m, 2H), thiadiazol-3-yl}piperazine-2.07-1.87(br., m, 4H) ppm 1-carboxamide 35 4-{4-[(2-amino-2- 512.48 5111.48 A (DMSO-d6) 9.29(s, 1H), 8.21(d, methylpropyl)oxy]-1,2,5- 2H),8.10(br., s, 2H), 7.60(s, 1H), thiadiazol-3-yl}-N-[3,5- 4.42(s, 2H),3.65-3.53(m, 8H), bis(trifluoromethyl)phenyl] 1.37(s, 6H) ppmpiperazine-1-carboxamide 36 N-[3,5- 531.48 532.0 1.95 B (CD₃OD) 8.55(d,2H), 8.22(s, bis(trifluoromethyl)phenyl]- 2H), 7.63(s, 1H), 7.50(d, 2H),1-{4-[(pyridin-4- 5.58(s, 2H), 4.32(m, 2H), ylmethyl)oxy]-1,2,5- 3.02(m,2H), 2.64(m, 1H), thiadiazol-3-yl}piperidine- 1.99-1.91(m, 4H) ppm4-carboxamide 37 1-{4-[(pyridin-4- 463.48 464.0 1.82 B (CD₃OD) 8.54(d,2H), 8.02(s, ylmethyl)oxy]-1,2,5- 1H), 7.74(d, 1H), 7.51-7.46(m,thiadiazol-3-yl}-N-[3- 3H), 7.36(d, 1H), 5.57(s, 2H),(trifluoromethyl)phenyl]piperidine- 4.32(m, 2H), 3.00(m, 2H),4-carboxamide 2.64(m, 1H), 1.96-1.90(m, 4H) ppm 38 N-[3,5- 526.44 525.11.78 A (CDCl3) 8.63(d, 2H), 7.90(s, bis(trifluoromethyl)phenyl]- 2H),7.81(d, 1H), 7.62(d, 1H), 4-{3-[(pyridin-4- 7.54(s, 1H), 7.34(d, 2H),7.26(s, ylmethyl)oxy]pyrazin-2- 2H), 6.78(s, 1H), 5.48(s, 2H),yl}piperazine-1- 3.67(m, 8H) ppm carboxamide 39 N-[3,5- 526.44 525.12.29 A (CDCl3) 8.62(d, 2H), 7.89(s, 2H), bis(trifluoromethyl)phenyl]-7.79(d, 2H), 7.61(d, 1H), 4-{3-[(pyridin-4- 7.34(dd, 2H), 6.93(s, 1H),5.47(s, 2H), ylmethyl)oxy]pyrazin-2- 3.67(m, 8H) ppm yl}piperazine-1-carboxamide 40 4-{3-[(pyridin-4- 458.44 459.1 1.71 A (CDCl3) 8.96(s,1H), 8.81(bs, ylmethyl)oxy]pyrazin-2- 2H), 7.94(s, 1H), 7.87(d, 1H),yl}-N-[3- 7.84(bs, 1H), 7.75(d, 1H), 7.63(d,(trifluoromethyl)phenyl]piperazine- 1H), 7.48(t, 1H), 7.29(d, 1H),1-carboxamide 5.64(s, 2H), 3.64(m, 4H), 3.57(m, 4H) ppm 41 N-[3,5-552.54 551.2 1.69 B (DMSO-d6) 9.29(s, 1H), 8.46(s,bis(trifluoromethyl)phenyl]- 1H), 8.20(s, 2H), 7.60(s, 1H),4-{4-[(2-piperidin-4- 4.50-4.42(m, 2H), 3.60(t, 4H), ylethyl)oxy]-1,2,5-3.50(t, 4H), 3.41-3.24(m, 2H), thiadiazol-3-yl}piperazine- 2.86-2.81(m,2H), 1.85(d, 2H), 1-carboxamide 1.76-1.75(m, 3H), 1.38-1.33(m, 2H) ppm42 2-methyl-4-{4-[(pyridin-4- 478.5 477.1 1.79 B (DMSO-d6) 8.83(s, 1H),8.59(s, ylmethyl)oxy]-1,2,5- 2H), 7.92(s, 1H), 7.75(m, 1H),thiadiazol-3-yl}-N-[3- 7.43(m, 3H), 7.24(m, 1H),(trifluoromethyl)phenyl]piperazine- 5.52(s, 2H), 4.47(s, 1H), 4.04(m,2H), 1-carboxamide 3.36(s, 1H), 3.25(t, 1H), 3.08(d, 1H), 2.97(t, 1H),1.20(m, 3H) ppm 43 1-phenyl-4-{4-[(pyridin-4- 353.45 354.1 1.78 B(DMSO-d₆) δ 8.62(d, 2H), ylmethyl)oxy]-1,2,5- 7.46(d, 2H), 7.23(t, 2H),7.01(d, 2H), thiadiazol-3-yl}piperazine 6.82(t, 1H), 5.58(s, 2H),3.64(m, 4H), 3.23(m, 4H) 44 1-[(4- 381.5 382.1 1.76 B (DMSO-d₆) δ8.57(d, 2H), methylphenyl)methyl]-4- 7.41(d, 2H), 7.19(d, 2H), 7.11(d,2H), {4-[(pyridin-4- 5.48(s, 2H), 3.49(m, 4H), 3.47(s,ylmethyl)oxy]-1,2,5- 2H), 2.44(m, 4H), 2.23(s, 3H)thiadiazol-3-yl}piperazine 45 N-[3,5- 531.48 532 1.9 B (DMSO-d6) 9.41(s,1H), 8.65(br, bis(trifluoromethyl)phenyl]- s, 2H), 8.2(s, 2H), 7.75(d,1H), 4-{4-[(pyridin-4- 7.6(s, 2H), 7.45(t, 1H), 4.65(d,ylmethyl)amino]-1,2,5- 2H), 3.65(m, 4H), 3.22(m, 4H)thiadiazol-3-yl}piperazine- 1-carboxamide 46 4-{4-[(pyridin-4- 478.5 4791.65 B (CDCl3) 8.639(s, 2H), 7.639(s, ylmethyl)oxy]-1,2,5- 1H),7.529-7.507(d, 1H), thiadiazol-3-yl}-N-[3- 7.408-7.368(t, 1H),7.319-7.305(d, 2H), (trifluoromethyl)phenyl]- 7.286(s, 1H), 6.552(s,1H), 1,4-diazepane-1- 5.464(s, 2H), 3.904-3.859(t, 2H), carboxamide3.844-3.829(t, 2H), 3.795-3.781(t, 2H), 3.587-3.556(t, 2H), 1.997(m, 2H)ppm 47 2-methyl-1-{[2- 425.51 426 2.05 A (CDCl3) 8.639(m, 2H),(methyloxy)phenyl]carbonyl}- 7.389-7.227(m, 4H), 7.026-6.920(m,4-{4-[(pyridin-4- 2H), 5.494(m, 2H), 5.077[br. s, ylmethyl)oxy]-1,2,5-1/2H(DS)], 4.714-4.708[d, thiadiazol-3-yl}piperazine 1/2H(DS)],4.209-3.937(br. m, 2H), 3.895-3.765(m, 4H), 3.412-2.991(m, 3H),1.403-1.26(m, 3H) ppm 48 N-[5-chloro-2- 460.94 461.1 2.12 B (CDCl₃)8.58(d, 2H), 8.17(s, 1H), (methyloxy)phenyl]-N′-(1- 7.27(d, 1H), 7.24(s,1H), 7.00(s, {4-[(pyridin-4- 1H), 6.87(d, 1H), 6.69(d, 1H),ylmethyl)oxy]-1,2,5- 5.41(s, 2H), 5.30(d, 1H),thiadiazol-3-yl}pyrrolidin- 4.52-4.50(m, 1H), 3.93-3.89(m, 1H),3-yl)urea 3.79-3.67(m, 3H), 2.28-2.24(m, 1H), 2.00-1.70(m, 1H), 1.70(s,3H) ppm 49 N-[5-methyl-2- 440.53 441.2 1.7 B (CDCl₃) 8.55(s, 2H),7.88(s, 1H), (methyloxy)phenyl]-N′-(1- 7.24(d, 2H), 7.16(s, 1H),{4-[(pyridin-4- 6.71-6.36(m, 2H), 5.88(d, 1H), 5.36(s,ylmethyl)oxy]-1,2,5- 2H), 4.50-4.48(m, 1H), thiadiazol-3-yl}pyrrolidin-3.91-3.87m, 1H), 3.75-3.64(m, 5H), 3-yl)urea 2.23-2.19(m, 4H),1.98-1.95(m, 2H) ppm 50 N-(1-{4-[(pyridin-4- 464.47 465.1 2.14 B(DMSO-d6) 8.57(d, 2H), 8.42(s, ylmethyl)oxy]-1,2,5- 1H), 7.87(s, 1H),7.77(s, 1H), thiadiazol-3-yl}pyrrolidin- 7.42-7.29(m, 3H), 7.13(d, 1H),3-yl)-N′-[3- 6.45(d, 1H), 5.47(d, 2H), 4.40(m,(trifluoromethyl)phenyl]urea 1H), 3.93-3.89(m, 1H), 3.84-3.73(m, 2H),3.67-3.64(m, 1H), 2.28-2.20(m, 1H), 2.02-1.96(s, 1H) ppm 512-methyl-N-[4-(1- 452.58 453 2.23 A (CDCl3) 8.651-8.590(br. m, 2H),methylethyl)phenyl]-4-{4- 7.332-7.259(m, 4H), [(pyridin-4-ylmethyl)oxy]-7.147-7.127(d, 2H), 6.69(s, 1H), 1,2,5-thiadiazol-3- 5.491-5478(dd, 2H),4.361(br. s, 1H), yl}piperazine-1- 4.116-4.027(m, 2H), 3.941-3.909(d,carboxamide 1H), 3.392-3.354(t, 1H), 3.134-3.095(d, 1H), 3.029-2.9(t,1H), 2.868-2.834(m, 1H), 1.326-1.309(d, 3H), 1.218-1.201(d, 6H) ppm 522-methyl-N-[3- 456.59 457 2.15 A (CDCl3) 8.654-8.640(d, 2H),(methylthio)phenyl]-4-{4- 7.359-7.321(m, 3H), [(pyridin-4-ylmethyl)oxy]-7.197-7.157(t, 1H), 7.110-7.087(d, 1H), 1,2,5-thiadiazol-3-6.929-6.908(d, 1H), 6.726(s, 1H), yl}piperazine-1- 5.528-5.447(m, 2H),4.366(br. s, 1H), carboxamide 4.127-4.035(m, 2H), 3.944-3.912(d, 1H),3.400-3.370(m, 1H), 3.138-3.098(m, 1H), 3.035-2.96(m, 1H), 2.451(s, 3H),1.337-1.321(d, 3H) ppm 53 (2R)-N-[3,5- 546.49 547 2.04 B (CDCl3) 8.81(d,2H), 7.92(s, bis(trifluoromethyl)phenyl]- 2H), 7.69(d, 2H), 7.54(s, 1H),2-methyl-4-{4-[(pyridin- 6.77(s, 1H), 5.65(d, 2H),4-ylmethyl)oxy]-1,2,5- 4.42(br., m, 1H), 4.18-3.95(m, 3H),thiadiazol-3-yl}piperazine- 3.34(br., m, 3H) 1.39(d, 3H) ppm1-carboxamide 54 (2R)-2-methyl-4-{4- 478.5 479 1.84 B (CDCl3) 8.83(d,2H), 7.71(d, [(pyridin-4-ylmethyl)oxy]- 2H), 7.68(s, 1H), 7.58(d, 1H),1,2,5-thiadiazol-3-yl}-N- 7.42(t, 1H), 7.31(d, 1H), 6.56(s, [3- 1H),5.66(d, 2H), 4.41(m, 1H), (trifluoromethyl)phenyl]piperazine-4.17-3.94(m, 3H) 3.47-3.05(m, 1-carboxamide 3H) ppm 551-[4-(4-{4-[(pyridin-4- 395.49 361.1 2.1 B (DMSO-d6) 8.87-8.57(m, 2H),ylmethyl)oxy]-1,2,5- 7.90(d, 2H), 7.79(d, 2H), 6.96(d,thiadiazol-3-yl}piperazin- 2H), 5.70(s, 2H), 3.65-3.63(m,1-yl)phenyl]ethanone 4H), 3.46-3.44(m, 4H), 2.49(s, 3H) ppm 562-(4-{4-[(pyridin-4- 355.42 356.1 2.06 B (DMSO-d6) 8.52(s, 2H), 8.36(s,ylmethyl)oxy]-1,2,5- 2H), 7.37(s, 2H), 6.58(s, 1H),thiadiazol-3-yl}piperazin- 5.47(s, 2H), 3.80(t, 4H), 3.51(t,1-yl)pyrimidine 4H) ppm 57 1-[2-nitro-4- 466.44 467.1 2.2 B (DMSO-d6)8.57(s, 2H), 8.17(s, (trifluoromethyl)phenyl]-4- 1H), 7.86(d, 1H),7.53(d, 1H), {4-[(pyridin-4- 7.47-7.42(m, 2H), 5.52(s, 2H),ylmethyl)oxy]-1,2,5- 3.65-3.63(t, 4H), 3.49-3.17(t, 4H)thiadiazol-3-yl}piperazine ppm 58 (2S)-N-[3,5- 546.49 547.1 2.23 A(CDCl3) 8.81(s, 2H), 7.94(s, 2H), bis(trifluoromethyl)phenyl]- 7.73(d,2H), 7.48(s, 1H), 7.43(s, 2-methyl-4-{4-[(pyridin- 1H), 5.66(d, 2H),4.47(m, 1H), 4-ylmethyl)oxy]-1,2,5- 4.15(d, 1H), 4.05(d, 2H), 3.46(m,thiadiazol-3-yl}piperazine- 1H), 3.16(d, 1H), 3.05(m, 2H) 1-carboxamideppm 59 (2S)-2-methyl-4-{4- 478.5 479.1 2.14 A (DMSO-d6) 8.81(d, 2H),7.74(d, [(pyridin-4-ylmethyl)oxy]- 2H), 7.68(s, 1H), 7.60(d, 1H),1,2,5-thiadiazol-3-yl}-N- 7.41(t, 2H), 7.27(m, 2H), 6.8(s, [3- 1H),5.66(d, 2H), 4.42(m, 1H), (trifluoromethyl)phenyl]piperazine- 4.15(d,1H), 4.05(d, 1H), 3.96(d, 1-carboxamide 1H), 3.42(m, 1H), 3.21(m, 1H),3.01(m, 1H) ppm 60 N-[3,5- 435.33 434.1 2.04 A (DMSO-d6) 9.27(d, 1H),8.86(d, bis(trifluoromethyl)phenyl]- 1H), 8.23(d, 2H), 7.92(d, 1H),4-(3-hydroxypyrazin-2- 7.63(d, 1H), 6.90(d, 1H), 3.76(m,yl)piperazine-1- 4H), 4.67(d, 4H) ppm carboxamide 61 2-[2,5- 531.48532.1 2.2 B (CDCl₃) 8.58(d, 2H), 7.78-7.75(s,bis(trifluoromethyl)phenyl]- 2H), 7.64(d, 1H), 7.28-7.24(m,N-(1-{4-[(pyridin-4- 2H), 5.95(d, 1H), 5.42(s, 2H), ylmethyl)oxy]-1,2,5-4.58-4.54(m, 1H), 3.90-3.87(m, thiadiazol-3-yl}pyrrolidin- 1H),3.79-3.67(m, 4H), 3-yl)acetamide 3.61-3.58(m, 1H), 2.30-2.21(m, 1H),1.97-1.89(m, 1H) ppm 62 1-{[2,5- 545.51 546 2.3 A (CDCl3) 8.645(br. s,2H), bis(trifluoromethyl)phenyl] 7.793-7.772(d, 1H), 7.648-7.626(m,acetyl}-2-methyl-4-{4- 2H), 7.318-7.305(s, 2H),[(pyridin-4-ylmethyl)oxy]- 5.512-5.430(m, 2H), 4.876[br. s, 1/2H1,2,5-thiadiazol-3- (DS)], 4.543-4.511[d, 1/2H(DS)], yl}piperazine4.163-3.871[m, 4.5H(DS)], 3.700-3.574(m, 1H), 3.168-2.877[m, 2.5H(DS)],1.418-1.257(m, 3H) ppm 63 N-[3,5- 540.47 539.1 2.32 A (CDCl3) 8.86(d,2H), 7.93(s, 2H), bis(trifluoromethyl)phenyl]- 7.83(m, 3H), 7.52(d, 2H),5.69(d, 2-methyl-4-{3-[(pyridin- 2H), 4.45(m, 1H), 4.24(d, 1H),4-ylmethyl)oxy]pyrazin-2- 4.13(d, 1H), 3.97(d, 1H), 3.46(m,yl}piperazine-1- 1H), 3.24(dd, 1H), 3.06(m, 1H) carboxamide ppm 642-methyl-4-{3-[(pyridin-4- 472.47 471.1 2.16 A (CDCl3) 8.84(d, 2H),7.85(s, 2H), ylmethyl)oxy]pyrazin-2- 7.83(d, 2H), 7.67(s, 1H), 7.59(d,yl}-N-[3- 1H), 7.59(d, 1H), 7.40(t, 1H),(trifluoromethyl)phenyl]piperazine- 7.36(d, 2H), 7.00(s, 1H), 5.69(d,2H), 1-carboxamide 4.44(m, 1H), 4.22(d, 1H), 4.12(d, 1H), 3.97(d, 1H),3.46(m, 1H), 3.22(dd, 1H), 3.06(m, 1H) ppm 65 N-[3,5- 554.49 553.1 2.39A (CDCl3) 8.87(d, 2H), 7.92(s, 2H), bis(trifluoromethyl)phenyl]- 7.83(m,4H), 7.51(d, 2H), 5.69(s, 2,6-dimethyl-4-{3- 2H), 4.37(m, 2H), 4.17(d,2H), [(pyridin-4- 3.15(m, 2H), 1.48(d, 5H)ppm ylmethyl)oxy]pyrazin-2-yl}piperazine-1- carboxamide 66 2,6-dimethyl-4-{3- 486.5 485.2 1.89 A(CDCl3) 8.76(s, 1H), 7.81(d, 1H), [(pyridin-4- 7.70(m, 3H), 7.61(d, 2H),7.54(d, ylmethyl)oxy]pyrazin-2- 2H), 5.62(s, 2H), 4.35(m, 2H), yl}-N-[3-4.17(d, 2H), 3.12(m, 3H), 1.37(d, (trifluoromethyl)phenyl]piperazine-3H), 1.29(m, 3H) ppm 1-carboxamide 67 N-(1-{3-[(pyridin-4- 458.44 4591.7 B (DMSO-d6) 8.80(m, 3H), 7.97(s, ylmethyl)oxy]pyrazin-2- 1H),7.90(d, 2H), 7.68(d, 1H), yl}pyrrolidin-3-yl)-N′-[3- 7.4(m, 2H), 7.3(d,1H), 7.2(m, 1H), (trifluoromethyl)phenyl]urea 6.8(d, 1H), 5.3(s, 2H),4.25(m, H), 3.9(m, 1H), 3.75(m, 2H), 3.6(m, 1H), 2.40(m, 1H), 1.85(m,1H) 68 N-[3,5- 526.44 527 1.85 B (DMSO-d6) 9.20(s, 1H), 8.75(d,bis(trifluoromethyl)phenyl]- 2H), 8.05(s, 2H), 7.85(d, 2H),N′-(1-{3-[(pyridin-4- 7.68(m, 1H), 7.55(s, 1H), 7.3(m,ylmethyl)oxy]pyrazin-2- 1H), 7.0(d, 1H), 5.3(s, 2H),yl}pyrrolidin-3-yl)urea 4.25(m, H), 3.9(m, 1H), 3.75(m, 2H), 3.6(m, 1H),2.40(m, 1H), 1.85(m, 1H) 69 N-[3,5- 560.52 561.1 2.47 A (CDCl₃) 8.67(d,2H), 7.91(s, 2H), bis(trifluoromethyl)phenyl]- 7.53(s, 1H), 7.36(d, 2H),6.74(s, 2,6-dimethyl-4-{4- 1H), 5.51(s, 2H), 4.31(m, 2H),[(pyridin-4-ylmethyl)oxy]- 4.10(d, 2H), 3.11(dd, 2H),1,2,5-thiadiazol-3- 1.47(d, 6H) ppm yl}piperazine-1- carboxamide 702,6-dimethyl-4-{4- 492.52 493.1 2.27 A (CDCl₃) 8.65(d, 2H), 7.69(s, 1H),[(pyridin-4-ylmethyl)oxy]- 7.59(d, 1H), 7.41(t, 1H), 7.35(d,1,2,5-thiadiazol-3-yl}-N- 2H), 7.30(d, 1H), 6.54(s, 1H), [3- 5.50(s,2H), 4.30(m, 2H), 4.10(d, (trifluoromethyl)phenyl]piperazine- 2H),3.10(dd, 2H), 1.45(d, 6H) 1-carboxamide ppm 71 N-[3,5- 540.47 541.1 2.33A (CDCl₃) 8.77(d, 2H), 7.94(s, 2H), bis(trifluoromethyl)phenyl]- 7.82(d,1H), 7.71(d, 2H), 7.52(d, 3-methyl-4-{3-[(pyridin- 1H), 7.49(s, 1H),7.23(s, 1H), 4-ylmethyl)oxy]pyrazin-2- 5.62(s, 2H), 4.60(m, 1H),yl}piperazine-1- 4.01(m, 1H), 3.97-3.86(m, 2H), carboxamide 3.52-3.45(m,2H), 3.34(m, 1H), 1.26(d, 3H) ppm 72 3-methyl-4-{3-[(pyridin-4- 472.47473.2 2.16 A (CDCl₃) 8.76(d, 2H), 7.81(d, 1H), ylmethyl)oxy]pyrazin-2-7.69(m, 3H), 7.60(d, 1H), 7.52(d, yl}-N-[3- 1H), 7.39(t, 1H), 7.27(d,1H), (trifluoromethyl)phenyl]piperazine- 6.94(s, 1H), 5.61(s, 2H),4.59(m, 1-carboxamide 1H), 4.05(m, 1H), 3.95(m, 1H), 3.85(m, 1H),3.48(m, 2H), 3.33(m, 1H), 1.27(d, 3H) ppm 73 N-[3,5- 524.46 525 1.98 B(CDCl3) 8.599-8.586(d, 2H), bis(trifluoromethyl)phenyl]- 7.855(s, 2H),7.559-7.452(d, 2H), 4-{2-[(pyridin-4- 7.390-7.377(d, 2H),ylmethyl)oxy]phenyl}piperazine- 7.021-6.888(m, 4H), 5.146(s, 2H),1-carboxamide 3.728-3.704(m, 4H), 3.149-3.125(m, 4H) ppm 744-{2-[(pyridin-4- 456.47 457 1.82 B (CDCl3) 8.615-8.601(d, 2H),ylmethyl)oxy]phenyl}-N- 7.634(s, 1H), 7.579-7.557(d, 1H), [3-7.378-7.364(d, 3H), (trifluoromethyl)phenyl]piperazine- 7.262-7.242(d,1H), 7.017-6.869(m, 5H), 1-carboxamide 5.144(s, 2H), 3.695-3.670(m, 4H),3.154-3.129(m, 4H) ppm 75 N-[3,5- 590.53 591.1 2.18 B (CDCl3) 8.63(d,2H), 7.91(s, 2H), bis(trifluoromethyl)phenyl]- 7.88(m, 2H), 7.65(m, 4H),2-methyl-4-{3-[(pyridin- 6.85(s, 1H), 5.63(s, 2H), 4.40(m, 3H), 4-4.01(d, 1H), 3.48(m, 1H), ylmethyl)oxy]quinoxalin- 3.31(dd, 1H), 3.08(m,1H), 1.38(d, 2-yl}piperazine-1- 3H) ppm carboxamide 76 N-[3,5- 540.47541 1.95 B (CDCl3) 8.616-8.603(d, 2H), bis(trifluoromethyl)phenyl]-7.821(s, 2H), 7.692-7.684(d, 1H), 4-{3-[(pyridin-4- 7.482(s, 1H),7.427-7.420(d, 1H), ylmethyl)oxy]pyrazin-2- 7.326-7.312(d, 2H), 6.962(s,1H), yl}-1,4-diazepane-1- 5.416(s, 2H), 3.969-3.912(m, 4H), carboxamide3.798-3.784(t, 2H), 3.584-3.555(t, 2H), 1.951-1.924(t, 2H) ppm 772-methyl-4-{3-[(pyridin-4- 522.53 523.1 1.97 B (CDCl3) 8.65(d, 1H),7.69(m, ylmethyl)oxy]quinoxalin- 7H), 7.49(m, 3H), 7.32(d, 1H),2-yl}-N-[3- 5.61(s, 2H), 4.39(m, 2H), 3.96(d,(trifluoromethyl)phenyl]piperazine- 1H), 3.49(m, 1H), 3.29(dd, 1H),1-carboxamide 3.08(m, 1H), 1.31(d, 3H) ppm 78 4-{3-[(pyridin-4- 472.47473 1.75 B (CDCl3) 8.583-8.570(d, 2H), ylmethyl)oxy]pyrazin-2-7.677-7.671(d, 1H), 7.590(s, 1H), yl}-N-[3- 7.502-7.482(d, 1H),(trifluoromethyl)phenyl]- 7.397-7.390(d, 1H), 7.358-7.318(t, 1H),1,4-diazepane-1- 7.301-7.287(d, 2H), 7.238-7.219(d, 1H), carboxamide6.731(s, 1H), 5.394(s, 2H), 3.941-3.873(m, 4H), 3.764-3.737(t, 2H),3.544-3.514(t, 2H), 1.939(t, 2H) ppm 79 N-[3,5- 554.49 555.1 2.08 B(CDCl₃) 8.79(d, 2H), 7.94-7.80(s, bis(trifluoromethyl)phenyl]- 2H),7.80(d, 1H), 7.76(s, 2H), 2,5-dimethyl-4-{3- 7.49-7.46(m, 2H), 7.08(s,1H), [(pyridin-4- 5.64(s, 2H), 4.68(m, 2H), 3.92(d,ylmethyl)oxy]pyrazin-2- 1H), 3.80(d, 1H), 3.63-3.57(m, yl}piperazine-1-2H), 1.34(d, 3H), 1.26(d, 3H) carboxamide ppm 80 2,5-dimethyl-4-{3-486.5 487.1 1.9 B (CDCl₃) 8.81(m, 2H), 7.80(d, [(pyridin-4- 1H), 7.76(m,1H), 7.69(s, 1H), ylmethyl)oxy]pyrazin-2- 7.58(d, 1H), 7.45(d, 1H),7.38(t, yl}-N-[3- 1H), 7.27(d, 1H), 6.74(s, 1H),(trifluoromethyl)phenyl]piperazine- 5.64(s, 2H), 4.68(s, 1H), 4.41(s,1-carboxamide 1H), 3.92(d, 1H), 3.76(d, 1H), 3.60(d, 2H), 1.33(d, 3H),1.27(d, 3H) ppm 81 (2S)-N-[3,5- 540.47 541.2 2.34 A (CDCl3) 8.62(d, 2H),7.88(s, 2H), bis(trifluoromethyl)phenyl]- 7.77(d, 1H), 7.57(d, 1H),7.51(s, 2-methyl-4-{3-[(pyridin- 1H), 7.33(d, 2H), 6.64(s, 1H),4-ylmethyl)oxy]pyrazin-2- 5.44(s, 2H), 4.32(m, 1H), 4.21(m,yl}piperazine-1- 2H), 3.95(d, 1H), 3.46(m, 1H), carboxamide 3.15(dd,1H), 3.03(m, 1H), 1.32(m, 3H) ppm 82 (2S)-2-methyl-4-{3- 472.47 473.21.79 B (CDCl3) 8.62(d, 2H), 7.88(s, 2H), [(pyridin-4- 7.77(d, 1H),7.57(d, 1H), 7.51(s, ylmethyl)oxy]pyrazin-2- 1H), 7.33(d, 2H), 6.64(s,1H), yl}-N-[3- 5.44(s, 2H), 4.32(m, 1H), 4.18(m,(trifluoromethyl)phenyl]piperazine- 2H), 3.91(d, 1H), 3.43(m, 1H),1-carboxamide 3.12(dd, 1H), 3.03(m, 1H), 1.27(m, 3H) ppm 83 N-[3,5-550.46 551 2.08 B (CDCl3) 8.26(d, 1H), 7.88(s,bis(trifluoromethyl)phenyl]- 2H), 7.53(s, 1H), 7.22(d, 1H),4-(4-{[(2-fluoropyridin-4- 6.98(s, 1H), 6.88(s, 1H), 5.53(s,yl)methyl]oxy}-1,2,5- 2H), 3.73-3.50(m, 8H) ppmthiadiazol-3-yl)piperazine- 1-carboxamide 84 N-[3,5- 566.91 567 2.12 B(CDCl3) 8.43(d, 1H), 7.90(s, bis(trifluoromethyl)phenyl]- 2H), 7.55(s,1H), 7.38(s, 1H), 4-(4-{[(2-chloropyridin-4- 6.68(s, 1H), 5.49(s, 2H),3.66(d, yl)methyl]oxy}-1,2,5- 8H) ppm thiadiazol-3-yl)piperazine-1-carboxamide 85 N-[3,5- 560.88 561 2.08 B (CDCl3) 8.41(d, 1H), 7.91(s,bis(trifluoromethyl)phenyl]- 2H), 7.82(d, 1H), 7.61(d, 1H),4-(3-{[(2-chloropyridin-4- 7.54(s, 1H), 7.39(s, 1H), 6.70(s,yl)methyl]oxy}pyrazin-2- 1H), 5.47(s, 2H), 3.70-3.65(m, yl)piperazine-1-8H) ppm carboxamide 86 N-[3,5- 595.44 596.1 2.21 B (CDCl₃) δ 7.87(s,2H), 7.51(s, bis(trifluoromethyl)phenyl]- 1H), 7.29-7.36(m, 2H),4-(2-{[(2,3,5,6- 7.16-7.21(m, 2H), 6.78(s, 1H), 5.90(br s,tetrafluoropyridin-4- 1H), 4.79(d, 2H), 3.71(m, 4H),yl)amino]methyl}phenyl)piperazine- 3.02(t, 4H) 1-carboxamide 87 N-[3,5-611.89 612.1 2.27 B (CDCl₃) δ 7.88(s, 2H), 7.52(s,bis(trifluoromethyl)phenyl]- 1H), 7.31-7.38(m, 2H),4-(2-{[(3-chloro-2,5,6- 7.15-7.22(m, 2H), 6.70(s, 1H), 5.88(br t,trifluoropyridin-4- 1H), 4.85(dd, 2H), 3.71(m, 4H),yl)amino]methyl}phenyl)piperazine- 3.02(t, 4H) 1-carboxamide 88 N-[3,5-611.36 613 2.55 B (CDCl3) 8.40(s, 1H), 7.95(s, 2H),bis(trifluoromethyl)phenyl]- 7.45(s, 2H), 7.25(m, 1H), 6.6(s,4-(4-{[(2-bromopyridin-4- 1H), 5.45(m, 2H), 3.6(m, 4H),yl)methyl]oxy}-1,2,5- 1.6(m, 4H) thiadiazol-3-yl)piperazine-1-carboxamide 89 N-[3,5- 605.34 607 2.1 B (CDCl3) 8.40(s, 1H), 7.95(s,2H), bis(trifluoromethyl)phenyl]- 7.8(s, 1H), 7.6(s, 1H), 7.58(m,4-(3-{[(2-bromopyridin-4- 2H), 7.24(m, 1H), 6.62(s, 1H),yl)methyl]oxy}pyrazin-2- 5.4(s, 2H), 3.6(m, 4H), 1.6(m, 4H)yl)piperazine-1- carboxamide 90 N-[3,5- 544.43 545.1 2.04 B (CDCl3)8.24(d, 1H), 7.91(s, bis(trifluoromethyl)phenyl]- 2H), 7.82(d, 1H),7.61(d, 1H), 4-(3-{[(2-fluoropyridin-4- 7.54(s, 1H), 7.22(d, 1H),6.98(s, yl)methyl]oxy}pyrazin-2- 1H), 6.73(d, 1H), 5.51(s, 2H),yl)piperazine-1- 3.70-3.65(m, 8H) ppm carboxamide 91 N-[3,5- 576.46 5771.95 B (CD3OD) 8.594(s, 2H), 8.073(s, bis(trifluoromethyl)phenyl]- 2H),7.555-7.534(m, 3H), 5.584(s, 4-{5,6-dicyano-3- 2H), 4.043-4.029(m, 4H),[(pyridin-4- 3.739-3.713(m, 4H) ppm ylmethyl)oxy]pyrazin-2-yl}piperazine-1- carboxamide 92 4-{5,6-dicyano-3-[(pyridin- 508.46 5091.81 B (CDCl3) 8.673(s, 2H), 7.653(s, 4-ylmethyl)oxy]pyrazin-2- 1H),7.582-7.560(d, 1H), yl}-N-[3- 7.420-7.380(t, 1H), 7.336-7.284(m, 3H),(trifluoromethyl)phenyl]piperazine- 6.965(s, 1H), 5.493(s, 2H),1-carboxamide 4.025-3.999(m, 4H), 3.693-3.667(m, 4H) ppm 93N-(3-ethylphenyl)-4-{3- 418.5 419 1.97 C [(pyridin-4-ylmethyl)oxy]pyrazin-2- yl}piperazine-1- carboxamide 94N-(3-ethylphenyl)-2,6- 446.55 447 2.00 C dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2- yl}piperazine-1- carboxamide 95N-(3-ethylphenyl)-2- 482.59 483 1.95 C methyl-4-{3-[(pyridin-4-ylmethyl)oxy]quinoxalin- 2-yl}piperazine-1- carboxamide 96 N-[3,5-524.47 525.2 2.22 B (DMSO-d₆) δ 9.34(s, 1H), 8.48(d,bis(trifluoromethyl)phenyl]- 2H), 8.23(s, 1H), 8.20(d, 1H),4-[3-(2-pyridin-4- 8.14(d, 2H), 7.58(s, 1H), 7.39(d, ylethyl)pyrazin-2-2H), 3.66(m, 4H), 3.13-3.43(m, yl]piperazine-1- 8H) carboxamide 97N-[3,5- 525.45 526.1 2.21 B (DMSO-d₆) δ 9.24(s, 1H), 8.60(d,bis(trifluoromethyl)phenyl]- 2H), 8.22(s, 2H), 7.84(d, 1H),4-{3-[(pyridin-4- 7.58(s, 1H), 7.46(d, 2H), 7.33(d, 1H),ylmethyl)oxy]pyridin-2- 6.92(dd, 1H), 5.23(s, 2H), yl}piperazine-1-3.62-3.68(m, 4H) 3.37-3.41(m, 4H) carboxamide 98 N-[3,5- 524.46 525.21.78 B (DMSO-d₆) δ 10.58(s, 1H), bis(trifluoromethyl)phenyl]- 8.28(d,2H), 8.17(s, 2H), 7.73(s, 1H), 4-{2-[(pyridin-4- 7.49(d, 1H), 7.38(t,1H), yloxy)methyl]phenyl}piperazine- 7.18-7.25(m, 4H), 5.39(s, 2H),1-carboxamide 3.80-3.85(m, 4H) 3.00-3.04(m, 4H) 994-[4-(2-Amino-pyridin-4- 547.49 (CD₃OD) δ 3.64(m, 4H), 3.71(m,ylmethoxy)- 4H), 5.58(s, 2H), 6.92(dd, 1H, J=2, [1,2,5]thiadiazol-3-yl]-6.4), 7.54(s, 1H), 7.84(dd, 1H, piperazine-1-carboxylic J=0.8, 6.8),8.08(s, 1H) acid (3,5-bis- trifluoromethyl-phenyl)- amide 100(4-{4-[4-(3,5-Bis- 647.6 (CDCl₃) δ 1.52(s, 9H), 3.71(m, trifluoromethyl-8H), 5.49(s, 2H), 6.77(s, 1H), phenylcarbamoyl)- 6.96(m, 1H), 7.53(s,1H), 7.89(s, piperazin-1-yl]- 2H), 7.93(s, 1H), 8.12(s, 1H),[1,2,5]thiadiazol-3- 8.27(d, 1H, J=4.8) yloxymethyl-pyridin-2-yl)-carbamic acid tert-butyl ester 101 (4-{4-[4-(3,5-Bis- 605.52 (DMSO-d₆) δ3.58-3.67(m trifluoromethyl- overlapping s, 11H), 5.54(s, 2H),phenylcarbamoyl)- 7.10(d, 1H, J=5.2), 7.62(s, 1H), piperazin-1-yl]-7.98(s, 1H), 8.22(s, 2H), 8.28(d, [1,2,5]thiadiazol-3- 1H, J=5.2),9.30(s, 1H), 10.31(s, yloxymethyl}-pyridin-2- 1H) yl)-carbamic acidmethyl esterAssays

For assay of activity, generally Tie-2, or a compound according to theinvention is non-diffusably bound to an insoluble support havingisolated sample-receiving areas (e.g., a microtiter plate, an array,etc.). The insoluble support may be made of any composition to which thecompositions can be bound, is readily separated from soluble material,and is otherwise compatible with the overall method of screening. Thesurface of such supports may be solid or porous and of any convenientshape. Examples of suitable insoluble supports include microtiterplates, arrays, membranes and beads. These are typically made of glass,plastic (e.g., polystyrene), polysaccharides, nylon or nitrocellulose,Teflon™, etc. Microtiter plates and arrays are especially convenientbecause a large number of assays can be carried out simultaneously,using small amounts of reagents and samples. The particular manner ofbinding of the composition is not crucial so long as it is compatiblewith the reagents and overall methods of the invention, maintains theactivity of the composition and is nondiffusable. Exemplary methods ofbinding include the use of antibodies (which do not sterically blockeither the ligand binding site or activation sequence when the proteinis bound to the support), direct binding to “sticky” or ionic supports,chemical crosslinking, the synthesis of the protein or agent on thesurface, etc. Following binding of the protein or agent, excess unboundmaterial is removed by washing. The sample receiving areas may then beblocked through incubation with bovine serum albumin (BSA), casein orother innocuous protein or other moiety.

One measure of inhibition is K_(i). For compounds with IC₅₀'s less than1 μM, the K_(i) or K_(d) is defined as the dissociation rate constantfor the interaction of the agent with a Tie-2. Exemplary compositionshave K_(i)'s of, for example, less than about 100 μM, less than about 10μM, less than about 1 μM, and further for example having K_(i)'s of lessthan about 100 nM, and still further, for example, less than about 10nM. The K_(i) for a compound is determined from the IC₅₀ based on threeassumptions. First, only one compound molecule binds to the enzyme andthere is no cooperativity. Second, the concentrations of active enzymeand the compound tested are known (i.e., there are no significantamounts of impurities or inactive forms in the preparations). Third, theenzymatic rate of the enzyme-inhibitor complex is zero. The rate data(i.e. compound concentration) are fitted to the equation:

$V = {V_{\max}{E_{0}\left\lbrack {I - \frac{\left( {E_{0} + I_{0} + K_{d}} \right) - {\sqrt{\left( {E_{0} + I_{0} + K_{d}} \right)^{2} - {4\; E_{0}}}I_{0}}}{2\; E_{0}}} \right\rbrack}}$where V is the observed rate, V_(max), is the rate of the free enzyme,I₀ is the inhibitor concentration, E₀ is the enzyme concentration, andK_(d) is the dissociation constant of the enzyme-inhibitor complex.

Another measure of inhibition is GI₅₀, defined as the concentration ofthe compound that results in a decrease in the rate of cell growth byfifty percent. Exemplary compounds have GI₅₀'s of, for example, lessthan about 1 mM, less than about 10 μM, less than about 1 μM, andfurther, for example, having GI₅₀'s of less than about 100 nM, stillfurther having GI₅₀'s of less than about 10 nM. Measurement of GI₅₀ isdone using a cell proliferation assay.

Tyrosine kinase activity is determined by 1) measurement ofkinase-dependent ATP consumption by in the presence of a genericsubstrate such as polyglutamine, tyrosine (pEY), byluciferase/luciferin-mediated chemiluminescence or; 2) incorporation ofradioactive phosphate derived from ³³P-ATP into a generic substratewhich has been adsorbed onto the well surface of polystyrene microtiterplates. Phosphorylated substrate products are quantified byscintillation spectrometry.

Structure Activity Relationships

Table 3 shows structure activity relationship data for selectedcompounds of the invention. Inhibition is indicated as IC₅₀ withfollowing key: A=IC₅₀ less than 50 nM, B=IC₅₀ greater than 50 nM, butless than or equal to 1000 nM, C=IC₅₀ greater than 1000 nM, but lessthan 10,000 nM, D=IC₅₀ 10,000 nM or greater, and “-”=no data available.The abbreviation for human enzyme, Tie-2, is defined as tyrosine kinasewith immunoglobulin and EGF repeats.

TABLE 3 Number Name IC₅₀ Tie-2 1N-[(1R,2S)-2-phenylcyclopropyl]-4-{4-[(pyridin-4- Cylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 2N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4- Aylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 3N-[4-chloro-3-(trifluoromethyl)phenyl]-4-{4-[(pyridin-4- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 4N-[4-(1-methylethyl)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]- C1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 5N-(3-bromophenyl)-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- Cthiadiazol-3-yl}piperazine-1-carboxamide 6N-[3-(methylthio)phenyl]-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- Cthiadiazol-3-yl}piperazine-1-carboxamide 7N-(3-ethylphenyl)-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- Bthiadiazol-3-yl}piperazine-1-carboxamide 8N-(3,5-dimethylphenyl)-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5- Bthiadiazol-3-yl}piperazine-1-carboxamide 94-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 10N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-methylquinolin-4- Dyl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 11N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[3- D(dimethylamino)phenyl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 12N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-(1H-indol-5-yloxy)- B1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 13N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(3-thienylmethyl)oxy]- D1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 14N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-morpholin-4- Dylethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 15N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[2-(1H-imidazol-1- —yl)ethyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 16N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(1-methylpiperidin-4- —yl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 17N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[4- D(methyloxy)phenyl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 184-[4-({[3,4-bis(methyloxy)phenyl]methyl}oxy)-1,2,5-thiadiazol- D3-yl]-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 194-{4-[(1,3-benzodioxol-5-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}- DN-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 20N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(furan-3- Dylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 21N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(tetrahydrofuran-3- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 22N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{4-[(pyridin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 23N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-1,4-diazepane-1- carboxamide 241-({[(1S,2R,5S)-5-methyl-2-(1- Cmethylethyl)cyclohexyl]oxy}acetyl)-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine 255-phenyl-N-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- Cyl}pyrrolidin-3-yl)-1,3-oxazole-4-carboxamide 261-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-4-{[3- —(trifluoromethyl)phenyl]acetyl}piperazine 27N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(piperidin-4- Dylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 28N-[3,5-bis(trifluoromethyl)phenyl]-N′-[(4-{4-[(pyridin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazin-1-yl)methyl]urea 29N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(3-pyridin-3- Cylpropyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 30N-[3,5-bis(trifluoromethyl)phenyl]-4-{1,1-dioxido-4-[(pyridin- —4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide 314-[4-(1-azabicyclo[2.2.2]oct-3-yloxy)-1,2,5-thiadiazol-3-yl]-N- —[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 324-[({4-[4-({[3,5- Cbis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]benzoic acid 33N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(piperidin-3- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 34N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-pyrrolidin-1- —ylethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 354-{4-[(2-amino-2-methylpropyl)oxy]-1,2,5-thiadiazol-3-yl}-N- —[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 36N-[3,5-bis(trifluoromethyl)phenyl]-1-{4-[(pyridin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperidine-4-carboxamide 371-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3- B(trifluoromethyl)phenyl]piperidine-4-carboxamide 38N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4- Aylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 394-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- A(trifluoromethyl)phenyl]piperazine-1-carboxamide 40N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(2-piperidin-4- —ylethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 412-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}- BN-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 421-phenyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- —yl}piperazine 431-[(4-methylphenyl)methyl]-4-{4-[(pyridin-4-ylmethyl)oxy]- —1,2,5-thiadiazol-3-yl}piperazine 44N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyridin-4- Cylmethyl)amino]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide 454-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}-N-[3- C(trifluoromethyl)phenyl]-1,4-diazepane-1-carboxamide 462-methyl-1-{[2-(methyloxy)phenyl]carbonyl}-4-{4-[(pyridin-4- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine 47N-[5-chloro-2-(methyloxy)phenyl]-N′-(1-{4-[(pyridin-4- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)urea 48N-[5-methyl-2-(methyloxy)phenyl]-N′-(1-{4-[(pyridin-4- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)urea 49N-(1-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- Cyl}pyrrolidin-3-yl)-N′-[3-(trifluoromethyl)phenyl]urea 502-methyl-N-[4-(1-methylethyl)phenyl]-4-{4-[(pyridin-4- Cylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 512-methyl-N-[3-(methylthio)phenyl]-4-{4-[(pyridin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 52(2R)-N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{4- B[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 53(2R)-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol- B3-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 541-[4-(4-{4-[(pyridin-4-ylmethy)oxy]-1,2,5-thiadiazol-3- —yl}piperazin-1-yl)phenyl]ethanone 552-(4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- —yl}piperazin-1-yl)pyrimidine 561-[2-nitro-4-(trifluoromethyl)phenyl]-4-{4-[(pyridin-4- —ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine 57(2S)-N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{4- B[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 58(2S)-2-methyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol- B3-yl}-N-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 59N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-hydroxypyrazin-2- —yl)piperazine-1-carboxamide 602-[2,5-bis(trifluoromethyl)phenyl]-N-(1-{4-[(pyridin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}pyrrolidin-3-yl)acetamide 611-{[2,5-bis(trifluoromethyl)phenyl]acetyl}-2-methyl-4-{4- B[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine 62N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{3-[(pyridin-4- Aylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 632-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 64N-[3,5-bis(trifluoromethyl)phenyl]-2,6-dimethyl-4-{3-[(pyridin- B4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 652,6-dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 66N-(1-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)- BN′-[3-(trifluoromethyl)phenyl]urea 67N-[3,5-bis(trifluoromethyl)phenyl]-N′-(1-{3-[(pyridin-4- Bylmethyl)oxy]pyrazin-2-yl}pyrrolidin-3-yl)urea 68N-[3,5-bis(trifluoromethyl)phenyl]-2,6-dimethyl-4-{4-[(pyridin- B4-ylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1- carboxamide 692,6-dimethyl-4-{4-[(pyridin-4-ylmethyl)oxy]-1,2,5-thiadiazol-3- Byl}-N-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 70N-[3,5-bis(trifluoromethyl)phenyl]-3-methyl-4-{3-[(pyridin-4- Aylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 713-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 72N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4- Aylmethyl)oxy]phenyl}piperazine-1-carboxamide 734-{2-[(pyridin-4-ylmethyl)oxy]phenyl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 74N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{3-[(pyridin-4- Bylmethyl)oxy]quinoxalin-2-yl}piperazine-1-carboxamide 75N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4- Bylmethyl)oxy]pyrazin-2-yl}-1,4-diazepane-1-carboxamide 762-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]quinoxalin-2-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 774-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- B(trifluoromethyl)phenyl]-1,4-diazepane-1-carboxamide 78N-[3,5-bis(trifluoromethyl)phenyl]-2,5-dimethyl-4-{3-[(pyridin- A4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 792,5-dimethyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 80(2S)-N-[3,5-bis(trifluoromethyl)phenyl]-2-methyl-4-{3- A[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1- carboxamide 81(2S)-2-methyl-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N- A[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 82N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-fluoropyridin-4- Cyl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 83N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-chloropyridin-4- Cyl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 84N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-chloropyridin-4- Byl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide 85N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(2,3,5,6- —tetrafluoropyridin-4-yl)amino]methyl}phenyl)piperazine-1- carboxamide 86N-[3,5-bis(trifluoromethyl)phenyl]-4-(2-{[(3-chloro-2,5,6- —trifluoropyridin-4-yl)amino]methyl}phenyl)piperazine-1- carboxamide 87N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-bromopyridin-4- Cyl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 88N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-bromopyridin-4- Byl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide 89N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-fluoropyridin-4- Byl)methyl]oxy}pyrazin-2-yl)piperazine-1-carboxamide 90N-[3,5-bis(trifluoromethyl)phenyl]-4-{5,6-dicyano-3-[(pyridin- B4-ylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 914-{5,6-dicyano-3-[(pyridin-4-ylmethyl)oxy]pyrazin-2-yl}-N-[3- B(trifluoromethyl)phenyl]piperazine-1-carboxamide 92N-(3-ethylphenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyrazin-2- Ayl}piperazine-1-carboxamide 93N-(3-ethylphenyl)-2-methyl-4-{3-[(pyridin-4- Aylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 94N-(3-ethylphenyl)-2,6-dimethyl-4-{3-[(pyridin-4- Bylmethyl)oxy]pyrazin-2-yl}piperazine-1-carboxamide 95N-(3-ethylphenyl)-2-methyl-4-{3-[(pyridin-4- Bylmethyl)oxy]quinoxalin-2-yl}piperazine-1-carboxamide 96N-[3,5-bis(trifluoromethyl)phenyl]-4-[3-(2-pyridin-4- Bylethyl)pyrazin-2-yl]piperazine-1-carboxamide 97N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4- Aylmethyl)oxy]pyridin-2-yl}piperazine-1-carboxamide 98N-[3,5-bis(trifluoromethyl)phenyl]-4-{2-[(pyridin-4- —yloxy)methyl]phenyl}piperazine-1-carboxamide 994-(4-{[(2-aminopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)- AN-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 1001,1-dimethylethyl {4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 101 methyl{4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 1024-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}pyridin- D2-amine 103 N-(4-chlorophenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-D yl}piperazine-1-carboxamide 1044-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 105N-(3-chlorophenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2- Byl}piperazine-1-carboxamide 1064-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3-yl)oxy]methyl}-N- Dpropylpyridin-2-amine 107 N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-B (propylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 108N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- A(methylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 109N-methyl-4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3- Dyl)oxy]methyl}pyridin-2-amine 110N-ethyl-4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3- —yl)oxy]methyl}pyridin-2-amine 111N-butyl-4-{[(4-piperazin-1-yl-1,2,5-thiadiazol-3- Dyl)oxy]methyl}pyridin-2-amine 112N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- A(methylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 113N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- A(ethylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 114N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- B(butylamino)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 115N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2- B[(phenylmethyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 116N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(1- Bmethylethyl)amino]pyrimidin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 117N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2- B[(phenylmethyl)amino]pyrimidin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 118N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- A(phenylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 119N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[2- B(dimethylamino)ethyl]amino}pyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 120N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[2- B(dimethylamino)ethyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 121N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- A(ethylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 122N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- B(propylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 123N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- A(cyclopropylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 1244-[4-({[2-(acetylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5- Athiadiazol-3-yl]-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 125 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2- C[(phenylcarbonyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 126N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2- B[(phenylcarbonyl)amino]pyrimidin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 1274-{4-[({2-[bis(phenylcarbonyl)amino]pyridin-4-yl}methyl)oxy]- —1,2,5-thiadiazol-3-yl}-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 128N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- B(cyclopentylamino)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 1294-[4-({[2-(acetylamino)pyridin-4-yl]methyl}oxy)-1,2,5- Athiadiazol-3-yl]-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 130 N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[({[3,5- Cbis(trifluoromethyl)phenyl]amino}carbonyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 131 methyl{4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyrimidin-2-yl}carbamate 1324-(4-{[(2-aminopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)- BN-(3-ethylphenyl)piperazine-1-carboxamide 133 methyl[4-({[4-(4-{[(3-ethylphenyl)amino]carbonyl}piperazin- A1-yl)-1,2,5-thiadiazol-3-yl]oxy}methyl)pyridin-2-yl]carbamate 134N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-cyanopyrimidin-4- Dyl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 1354-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N- A[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 1364-[({4-[4-({[3,5- Bbis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyrimidine-2-carboxamide 137N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2- D(butyloxy)pyrimidin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 138N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[(pyrimidin-4- Bylmethyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 1394-[({4-[4-({[3,5- Dbis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridine-2-carboxylic acid 1402-pyrrolidin-1-ylethyl {4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 1412-morpholin-4-ylethyl {4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 1424-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- A[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 143N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[(1- Amethylpiperidin-3-yl)carbonyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 1444-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Aethylphenyl)piperazine-1-carboxamide 145 2-(4-methylpiperazin-1-yl)ethyl{4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 146N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[(1- Aethylpiperidin-4-yl)carbonyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 1474-(4-{[(2-aminopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)- AN-{3-[(trifluoromethyl)thio]phenyl}piperazine-1-carboxamide 1484-({[4-(4-{[3,5-bis(trifluoromethyl)phenyl]sulfonyl}piperazin-1- Dyl)-1,2,5-thiadiazol-3-yl]oxy}methyl)pyridin-2-amine 1494-(4-{[(2-aminopyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)- DN-naphthalen-1-ylpiperazine-1-carboxamide 150N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(N,N- Adimethylglycyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 151N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(morpholin-4- Aylacetyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 152N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(piperidin-1- Bylacetyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 153 ethyl {4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 154N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(pyrrolidin-1- Aylacetyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 155N-[3,5-bis(trifluoromethyl)phenyl]-4-(4-{[(2-{[(4- Amethylpiperazin-1-yl)acetyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 156N-[3,5-bis(trifluoromethyl)phenyl]-4-{4-[({2-[(N,N- Bdiethylglycyl)amino]pyridin-4-yl}methyl)oxy]-1,2,5-thiadiazol-3-yl}piperazine-1-carboxamide 157 1-ethylpiperidin-4-yl{4-[({4-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 1584-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-(3-ethylphenyl)piperazine-1-carboxamide 159N-[3,5-bis(trifluoromethyl)phenyl]-4-[4-({[2-(2-oxo-1,3- Doxazolidin-3-yl)pyridin-4-yl]methyl}oxy)-1,2,5-thiadiazol-3-yl]piperazine-1-carboxamide 160 2-(diethylamino)ethyl {4-[({4-[4-({[3,5-A bis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyridin-2-yl}carbamate 161 methyl[4-({[2-(4-{[(3-ethylphenyl)amino]carbonyl}piperazin- A1-yl)pyridin-3-yl]oxy}methyl)pyridin-2-yl]carbamate 1622-pyrrolidin-1-ylethyl {4-[({4-[4-({[3,5- Bbis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyrimidin-2-yl}carbamate 1632-piperidin-1-ylethyl {4-[({4-[4-({[3,5- Bbis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]-1,2,5-thiadiazol-3-yl}oxy)methyl]pyrimidin-2-yl}carbamate 164 methyl[4-({[2-(4-{[(3-bromophenyl)amino]carbonyl}piperazin- A1-yl)pyridin-3-yl]oxy}methyl)pyridin-2-yl]carbamate 165 methyl{4-[({2-[4-({[3- B(methyloxy)phenyl]amino}carbonyl)piperazin-1-yl]pyridin-3-yl}oxy)methyl]pyridin-2-yl}carbamate 1664-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- B(methyloxy)phenyl]piperazine-1-carboxamide 1674-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- A(1-methylethyl)phenyl]piperazine-1-carboxamide 1684-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-{3- A[(trifluoromethyl)oxy]phenyl}piperazine-1-carboxamide 1694-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2- Afluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 170N-(3-ethylphenyl)-4-[3-({[2-({[(3- Aethylphenyl)amino]carbonyl}amino)pyridin-4-yl]methyl}oxy)pyridin-2-yl]piperazine-1-carboxamide 171N-(3-ethylphenyl)-4-(3-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 172N-(3-ethylphenyl)-4-(4-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 173N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4- Amethylpiperazin-1-yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 1744-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- A(trifluoromethyl)phenyl]piperazine-1-carboxamide 1754-[3-({[2-(acetylamino)pyridin-4-yl]methyl}oxy)pyridin-2-yl]- AN-(3-ethylphenyl)piperazine-1-carboxamide 1764-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Aethyl-4-fluorophenyl)piperazine-1-carboxamide 1772-[4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2- Cyl)piperazin-1-yl]-N-[3,5-bis(trifluoromethyl)phenyl]acetamide 1784-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- Cphenylpiperazine-1-carboxamide 1794-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Achloro-5-ethylphenyl)piperazine-1-carboxamide 1804-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(5- Aethyl-2-fluorophenyl)piperazine-1-carboxamide 1814-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Abromo-5-ethylphenyl)piperazine-1-carboxamide 1822-(4-methylpiperazin-1-yl)ethyl [4-({[2-(4-{[(3- Aethylphenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2-yl]carbamate 1834-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Bchlorophenyl)piperazine-1-carboxamide 1844-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Abromophenyl)piperazine-1-carboxamide 185N-[4-({[2-(4-acetylpiperazin-1-yl)pyridin-3- Dyl]oxy}methyl)pyridin-2-yl]-2-(4-methylpiperazin-1- yl)acetamide 1864-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Bfluorophenyl)piperazine-1-carboxamide 1874-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(4- Cfluorophenyl)piperazine-1-carboxamide 1884-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(2- Cfluorophenyl)piperazine-1-carboxamide 1894-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- A(3,5-diethylphenyl)piperazine-1-carboxamide 1904-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}-5-bromopyridin-2- Ayl)-N-(3-ethylphenyl)piperazine-1-carboxamide 191N-methyl-4-(3-{[(2-{[(4-methylpiperazin-1- Cyl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 1924-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2- Achloro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 1934-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(5- Bchloro-2-fluorophenyl)piperazine-1-carboxamide 1944-(3-{[(2-amino-5-bromopyrimidin-4-yl)methyl]oxy}-5- Abromopyridin-2-yl)-N-(3-ethylphenyl)piperazine-1-carboxamide 1954-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[2- Bfluoro-3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 1964-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- Afluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 1974-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- A(3,5-dichlorophenyl)piperazine-1-carboxamide 198N-(3-chloro-5-ethylphenyl)-4-(3-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 199N-(5-ethyl-2-fluorophenyl)-4-(3-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 2004-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- Aethyl-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2014-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-(3- Aethylphenyl)piperazine-1-carboxamide 2024-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-(3- Achloro-5-ethylphenyl)piperazine-1-carboxamide 2034-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-(5- Aethyl-2-fluorophenyl)piperazine-1-carboxamide 2044-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- Dmethylpiperazine-1-carboxamide 2054-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- Dethylpiperazine-1-carboxamide 2064-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- Ccyclohexylpiperazine-1-carboxamide 2074-({[2-(4-acetylpiperazin-1-yl)pyridin-3- Dyl]oxy}methyl)pyrimidin-2-amine 2084-({[2-(4-propanoylpiperazin-1-yl)pyridin-3- Dyl]oxy}methyl)pyrimidin-2-amine 209N-(3-cyclopropylphenyl)-4-(3-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 2104-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Acyclopropylphenyl)piperazine-1-carboxamide 211N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4- Bmethylpiperazin-1-yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 212N-[3-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4- Amethylpiperazin-1-yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 213N-(3,5-dichlorophenyl)-4-(3-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 2144-(3-{[(2-{[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- Ayl)methyl]oxy}pyridin-2-yl)-N-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2154-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N- A(3,5-diethylphenyl)piperazine-1-carboxamide 2164-(3-{[1-(2-aminopyrimidin-4-yl)ethyl]oxy}pyridin-2-yl)-N- A[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 2174-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N- A(3,5-dichlorophenyl)piperazine-1-carboxamide 2184-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[3- Afluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2194-[({2-[4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperazin-1- Dyl]pyridin-3-yl}oxy)methyl]pyrimidin-2-amine 2204-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(2- Dmethylpropyl)piperazine-1-carboxamide 2214-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-(3-chloro-5-ethylphenyl)piperazine-1-carboxamide 2224-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-(5-ethyl-2-fluorophenyl)piperazine-1-carboxamide 2234-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-(3,5-dichlorophenyl)piperazine-1-carboxamide 2244-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N- Bphenylpiperazine-1-carboxamide 2254-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[2- Afluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 226N-(3,5-diethylphenyl)-4-(3-{[(2-{[(4-methylpiperazin-1- Ayl)acetyl]amino}pyridin-4-yl)oxy]methyl}pyridin-2-yl)piperazine-1-carboxamide 2274-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}-6-methylpyridin-2- Ayl)-N-(3-ethylphenyl)piperazine-1-carboxamide 2284-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}-6-methylpyridin-2- Ayl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 2294-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[3- A(trifluoromethyl)phenyl]piperazine-1-carboxamide 2304-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Dyl)-N-phenylpiperazine-1-carboxamide 2314-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2324-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide 233N-[3-chloro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4- Amethylpiperazin-1-yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 2344-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[3- Achloro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2354-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- Achloro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2364-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-(3- Abromo-5-ethylphenyl)piperazine-1-carboxamide 2374-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}-6-chloropyridin-2- Ayl)-N-(3-ethylphenyl)piperazine-1-carboxamide 2384-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-(3-bromo-5-ethylphenyl)piperazine-1-carboxamide 2394-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide 2404-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3-chloro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide 2414-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-(3- Aethyl-4-fluorophenyl)piperazine-1-carboxamide 2424-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-(3,5-diethylphenyl)piperazine-1-carboxamide 243N-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4- Amethylpiperazin-1-yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide 2444-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}-6-chloropyridin-2- Ayl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 2454-(3-{[1-(2-aminopyrimidin-4-yl)ethyl]oxy}pyridin-2-yl)-N-(3- Aethylphenyl)piperazine-1-carboxamide 2464-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}-6-chloropyridin-2- Ayl)-N-(5-ethyl-2-fluorophenyl)piperazine-1-carboxamide 2474-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-(3- Aethyl-5-fluorophenyl)piperazine-1-carboxamide 2484-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3-chloro-2-fluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2494-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- Achloro-2-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide 2504-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)-N- A[3,5-bis(trifluoromethyl)phenyl]-N-methylpiperazine-1- carboxamide 2514-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyrazin-2-yl)-N-[3- A(1-methylethyl)phenyl]piperazine-1-carboxamide 2524-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-(3-ethyl-4-fluorophenyl)piperazine-1-carboxamide 2534-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Cyl)-N-(3-chloro-4-fluorophenyl)piperazine-1-carboxamide 2544-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Cyl)-N-[2,5-bis(methyloxy)phenyl]piperazine-1-carboxamide 2554-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-[3,5- Abis(trifluoromethyl)phenyl]piperazine-1-carboxamide 2564-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-(3- Aethylphenyl)piperazine-1-carboxamide 2574-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Cyl)-N-(5-chloro-2-fluorophenyl)piperazine-1-carboxamide 2584-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-{3-[(trifluoromethyl)oxy]phenyl}piperazine-1- carboxamide 2594-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-[3-(methyloxy)phenyl]piperazine-1-carboxamide 2604-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3-ethyl-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide 2614-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3-(1-methylethyl)phenyl]piperazine-1-carboxamide 2624-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-[2-chloro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide 2634-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Cyl)-N-(3-fluorophenyl)piperazine-1-carboxamide 2644-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Dyl)-N-[2-(ethyloxy)phenyl]piperazine-1-carboxamide 2654-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Dyl)-N-(3,4-difluorophenyl)piperazine-1-carboxamide 2664-(4-{[(2-aminopyrimidin-4-yl)methyl]oxy}-1,2,5-thiadiazol-3- Byl)-N-[3-(methylthio)phenyl]piperazine-1-carboxamide 267N-(3-acetylphenyl)-4-(4-{[(2-aminopyrimidin-4- Cyl)methyl]oxy}-1,2,5-thiadiazol-3-yl)piperazine-1-carboxamide 2684-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-[2- Afluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2694-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-(3- Cfluorophenyl)piperazine-1-carboxamide 2704-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N- Cphenylpiperazine-1-carboxamide 2714-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-(3,5- Adichlorophenyl)piperazine-1-carboxamide 2724-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-[3- Afluoro-5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2734-[4-({[6,7-bis(methyloxy)quinolin-4-yl]methyl}oxy)-1,2,5- Athiadiazol-3-yl]-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 2744-({[4-(4-{[3,5-bis(trifluoromethyl)phenyl]acetyl}piperazin-1- Byl)-1,2,5-thiadiazol-3-yl]oxy}methyl)pyrimidin-2-amine 2755-{[(2-aminopyrimidin-4-yl)methyl]oxy}-6-[4-({[3,5- Abis(trifluoromethyl)phenyl]amino}carbonyl)piperazin-1-yl]pyrazine-2-carboxamide 2764-(4-{[6,7-bis(methyloxy)quinolin-4-yl]oxy}-1,2,5-thiadiazol-3- Ayl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1-carboxamide 2774-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-[3-ethyl- A5-(trifluoromethyl)phenyl]piperazine-1-carboxamide 2784-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-(5-ethyl- A2-fluorophenyl)piperazine-1-carboxamide 2794-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-(3,5- Adiethylphenyl)piperazine-1-carboxamide 2804-[({4-[4-(naphthalen-2-ylacetyl)piperazin-1-yl]-1,2,5- Dthiadiazol-3-yl}oxy)methyl]pyrimidin-2-amine 2814-(2-{[(2-aminopyrimidin-4-yl)methyl]oxy}phenyl)-N-(3- Achloro-5-ethylphenyl)piperazine-1-carboxamide

1. A compound of Formula I,

or a pharmaceutically acceptable salt thereof, wherein, Ar is selectedfrom the following formulae

wherein Ar is substituted with —X and —Y-L-Z, in an ortho relationshipto each other, and said Ar is optionally substituted with up to four R¹;each R¹ is independently selected from —H, halogen, —CN, —NO₂, —OR³,—N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, —OC(O)R³, optionally substitutedlower alkyl, optionally substituted aryl, optionally substituted lowerarylalkyl, optionally substituted heterocyclyl, and optionallysubstituted lower heterocyclylalkyl; X is selected from the followingformulae

wherein R^(4a) is —C(O)N(R³)R³; n=1 or 2; p=0 or 1; q is 1 to 3; M is−OR³ or —N(R³)R⁴; each R² is independently selected from —H, haloalkyl,—C₁₋₆alkyl-N(R³)R³, —C₁₋₆alkyl-OR³, —C₁₋₆alkyl-CO₂R³, and—C₁₋₆alkyl-C(O)N(R³)R³; each R³ is independently selected from —H,optionally substituted lower alkyl, optionally substituted aryl,optionally substituted lower arylalkyl, optionally substitutedheterocyclyl, and optionally substituted lower heterocyclylalkyl; or twoof R³, when taken together with a common nitrogen to which they areattached, form an optionally substituted five- to seven-memberedheterocyclyl ring, said optionally substituted five- to seven-memberedheterocyclyl ring optionally containing at least one additionalheteroatom selected from N, O, S, and P; each R⁴ is independentlyselected from R³, —SO₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, and—C(O)R³; Y-L-Z is selected from the following formulae,

wherein g is zero to two; T is selected from absent, —N(R³)—, —S— and—O—; and each methylene between Y and T is optionally substituted;provided that when both Y and T are heteroatoms then g must be two; Y is—O— or optionally substituted —CH₂—; R⁵ is selected from —H, halogen,—CN, —NO₂, —OR³, —N(R³)R⁴, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³,—C(O)N(R³)R³, —N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³,optionally substituted lower alkyl, optionally substituted aryl,optionally substituted lower arylalkyl, optionally substitutedheterocyclyl, and optionally substituted lower heterocyclylalkyl; andoptionally two of R⁵, together with the atoms to which they areattached, form a second ring system fused with said five- toseven-membered ring system, said second ring system substituted withzero to four of R⁵.
 2. The compound according to claim 1, wherein g isone or two.
 3. The compound according to claim 2, wherein each R⁵ isindependently selected from —H, halogen, —CN, —NH₂, —NO₂, —OR³,—N(R³)R⁴, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, and optionally substituted loweralkyl.
 4. The compound according to claim 3, wherein —Y-L-Z is selectedfrom the following formulae

wherein R^(4b) is selected from R³, H, CO₂R³, C(O)N(R³)R³, and C(O)R³.5. The compound according to claim 4, having formula III,

wherein J is N, and B is ═N— or ═C(R⁵)—. R^(3a) is selected fromoptionally substituted aryl, optionally substituted lower arylalkyl,optionally substituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl; R^(3b) is H, and R^(4b) is R³, —H, —CO₂R³,—C(O)N(R³)R⁴, or —C(O)R³.
 6. The compound according to claim 5, whereinR^(3a) is selected from optionally substituted aryl and optionallysubstituted heteroaryl.
 7. The compound according to claim 6, whereinR^(3a) is optionally substituted phenyl.
 8. The compound according toclaim 7, wherein said optionally substituted phenyl is substituted withat least one of halogen, —CN, —CF₃, —NH₂, —NO₂, —OR³, —N(R³)R³,—S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl,and optionally substituted aryl.
 9. The compound according to claim 8,wherein said optionally substituted phenyl group is substituted with atleast one trifluoromethyl group.
 10. The compound according to claim 9,wherein said optionally substituted phenyl group is substituted with atleast two trifluoromethyl groups.
 11. The compound according to claim 8,wherein said optionally substituted phenyl group is substituted with atleast one lower alkyl group.
 12. The compound according to claim 8,wherein R^(3b) is —H.
 13. The compound according to claim 12, whereinR^(4b) is selected from R³, —H, —CO₂R³, —C(O)N(R³)R⁴, and —C(O)R³. 14.The compound according to claim 13, wherein Ar is according to theformula below


15. The compound according to claim 13, wherein Ar is according to theformula below


16. A compound of Formula IV,

or a pharmaceutically acceptable salt thereof, wherein, Ar is selectedfrom the following formulae:

each R¹ is independently selected from —H, halogen, —CN, —NO₂, —OR³,—N(R³)R³, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³, —N(R³)SO₂R³,—N(R³)C(O)R³, —N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted lower arylalkyl,optionally substituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl; optionally two of R¹, together with the atoms towhich they are attached, form a first ring system fused with Ar, saidfirst ring system substituted with zero to three additional of R¹; eachR² is independently selected from —H, halogen, oxo, —CN, —NH₂, —NO₂,—OR³, —N(R³)R³, —N(R³)R⁵, —S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R³,—N(R³)SO₂R³, —N(R³)C(O)R³, —N(R³)CO₂R³, —N(R³)C(O)N(R³)R³, —C(O)R³,optionally substituted lower alkyl, optionally substituted aryl,optionally substituted lower arylalkyl, optionally substitutedheterocyclyl, and optionally substituted lower heterocyclylalkyl; two ofR², together with the atoms to which they are attached, can form anoptionally substituted three- to seven-membered ring system; each R³ isindependently selected from —H, optionally substituted lower alkyl,optionally substituted aryl, optionally substituted lower arylalkyl,optionally substituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl; or two of R³, when taken together with a commonnitrogen to which they are attached, form an optionally substitutedfive- to seven-membered heterocyclyl ring, said optionally substitutedfive- to seven-membered heterocyclyl ring optionally containing at leastone additional heteroatom selected from N, O, S, and P; each R⁴ isindependently selected from R³, —SO₂R³, —SO₂N(R³)R³, —CO₂R³,—C(O)N(R³)R³, and —C(O)R³; Y is selected from optionally substituted—CH₂—, —O—, —S—, and —N(R³)—; L is selected from optionally substituted—CH₂—, —O—, —S—, —N(R³)— and absent; provided that Y and L are not bothheteroatoms; B is ═N— or ═C(H)—; at each instance, R⁵ and R⁶ areindependently selected from —H, halogen, —CN, —NO₂, —OR³, —N(R³)R⁴,—S(O)₀₋₂R³, —SO₂N(R³)R³, —CO₂R³, —C(O)N(R³)R, —N(R³)SO₂R³, —N(R³)C(O)R³,—N(R³)CO₂R³, —C(O)R³, optionally substituted lower alkyl, optionallysubstituted aryl, optionally substituted lower arylalkyl, optionallysubstituted heterocyclyl, and optionally substituted lowerheterocyclylalkyl; and optionally two of R⁵, together with the atoms towhich they are attached, form a ring system fused with the ringcontaining B according to formula IV, said ring system substituted withzero to two additional of R⁵.
 17. The compound according to claim 16,wherein Y is —O— and L is optionally substituted —CH₂—.
 18. The compoundaccording to claim 17, wherein at least one of R⁶ is optionallysubstituted lower alkyl.
 19. The compound according to claim 18, whereinsaid at least one optionally substituted lower alkyl is meta- to thepiperazine urea function as depicted in formula IV.
 20. The compoundaccording to claim 19, wherein R^(4a) is selected from R³, —H, —CO₂R³,—C(O)N(R³)R⁴, and —C(O)R³.
 21. The compound according to claim 20,wherein R^(4a) is selected from —H, —CO₂R³, —C(O)N(R³)R⁴, and —C(O)R³.22. The compound according to claim 21, wherein —Y-L- is —OCH₂—.
 23. Thecompound according to claim 22, wherein Ar is according to the formulabelow


24. The compound according to claim 22, wherein Ar is according to theformula below


25. A compound selected from Table
 4. TABLE 4 97N-[3,5-bis(trifluoromethyl)phenyl]-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2- yl}piperazine-1-carboxamide

103 N-(4-chlorophenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]yridin-2-yl}piperazine- 1-carboxamide

105 N-(3-chlorophenyl)-4-{3-[(pyridin-4-ylmethyl)oxy]pyridin-2-yl}piperazine- 1-carboxamide

142 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

144 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethylphenyl)piperazine-1-carboxamide

161 methyl {4-({[2-(4-{[(3- methylphenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]carbamate

164 methyl [4-({[2-(4-{[(3- bromophenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin- 2-yl]carbamate

165 methyl {4-[({2-[4-({[3- (methyloxy)phenyl]amino}carbonyl)pipe-razin-1-yl]pyridin-3- yl}oxy)methyl]pyridin-2-yl}carbamate

166 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(methyloxy)phenyl]piperazine-1- carboxamide

167 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(1-methylethyl)phenyl]piperazine-1- carboxamide

168 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-{3-[(trifluoromethyl)oxy]phenyl}piperazine- 1-carboxamide

169 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2-fluoro-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

170 N-(3-ethylphenyl)-4-[3-({[2-({[(3-ethylphenyl)amino]carbonyl}amino)pyri- din-4-yl]methyl}oxy)pyridin-2-yl]piperazine-1-carboxamide

171 N-(3-ethylphenyl)-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

173 N-[3,5-bis(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

174 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-(trifluoromethyl)phenyl]piperazine-1- carboxamide

175 4-[3-({[2-(acetylamino)pyridin-4- yl]methyl}oxy)pyridin-2-yl]-N-(3-ethylphenyl)piperazine-1-carboxamide

176 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethyl-4-fluorophenyl)piperazine-1- carboxamide

177 2-[4-(3-{[(2-aminopyrimidin-4-yl)methyl]oxy}pyridin-2-yl)piperazin-1- yl]-N-[3,5-bis(trifluoromethyl)phenyl]acetamide

178 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-phenylpiperazine-1-carboxamide

179 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-chloro-5-ethylphenyl)piperazine-1- carboxamide

180 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide

181 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-bromo-5-ethylphenyl)piperazine-1- carboxamide

182 2-(4-methylpiperazin-1-yl)ethyl [4-({[2- (4-{[(3-ethylphenyl)amino]carbonyl}piperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2- yl]carbamate

183 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-chlorophenyl)piperazine-1-carboxamide

184 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-bromophenyl)piperazine-1-carboxamide

185 N-[4-({[2-(4-acetylpiperazin-1-yl)pyridin-3-yl]oxy}methyl)pyridin-2-yl]-2-(4-methylpiperazin-1-yl)acetamide

186 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-fluorophenyl)piperazine-1-carboxamide

187 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(4-fluorophenyl)piperazine-1-carboxamide

188 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(2-fluorophenyl)piperazine-1-carboxamide

189 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3,5-diethylphenyl)piperazine-1-carboxamide

190 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-5-bromopyridin-2-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

191 N-methyl-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

192 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

193 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(5-chloro-2-fluorophenyl)piperazine-1- carboxamide

194 4-(3-{[(2-amino-5-bromopyrimidin-4-yl)methyl]oxy}-5-bromopyridin-2-yl)- N-(3-ethylphenyl)piperazine-1-carboxamide

195 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[2-fluoro-3- (trifluoromethyl)phenyl]piperazine-1- carboxamide

196 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

197 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3,5-dichlorophenyl)piperazine-1- carboxamide

198 N-(3-chloro-5-ethylphenyl)-4-(3-{[(2- {[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

199 N-(5-ethyl-2-fluorophenyl)-4-(3-{[(2- {[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

200 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-ethyl-5-(trifluoromethyl)phenyl]piperazine-1- carboxamide

204 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-methylpiperazine-1-carboxamide

205 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-ethylpiperazine-1-carboxamide

206 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-cyclohexylpiperazine-1-carboxamide

207 4-({[2-(4-acetylpiperazin-1-yl)pyridin-3-yl]oxy}methyl)pyrimidin-2-amine

208 4-({[2-(4-propanoylpiperazin-1-yl)pyridin-3-yl]oxy}methyl)pyrimidin- 2-amine

209 N-(3-cyclopropylphenyl)-4-(3-{[(2- {[(4-methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

210 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-cyclopropylphenyl)piperazine-1- carboxamide

211 N-[2-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

212 N-[3-fluoro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

213 N-(3,5-dichlorophenyl)-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)methyl]oxy}pyridin-2-yl)piperazine-1-carboxamide

214 4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)-N-[3- (trifluoromethyl)phenyl]piperazine-1-carboxamide

216 4-(3-{[1-(2-aminopyrimidin-4- yl)ethyl]oxy}pyridin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

219 4-[({2-[4-(3,4-dihydroquinolin-1(2H)-ylcarbonyl)piperazin-1-yl]pyridin-3- yl}oxy)methyl]pyrimidin-2-amine

220 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(2-methylpropyl)piperazine-1-carboxamide

226 N-(3,5-diethylphenyl)-4-(3-{[(2-{[(4- methylpiperazin-1-yl)acetyl]amino}pyridin-4- yl)oxy]methyl}pyridin-2-yl)piperazine-1-carboxamide

227 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-methylpyridin-2-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

228 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-methylpyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

233 N-[3-chloro-5-(trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

235 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-chloro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

237 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)-N-(3-ethylphenyl)piperazine-1- carboxamide

243 N-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]-4-(3-{[(2-{[(4-methylpiperazin-1- yl)acetyl]amino}pyridin-4-yl)methyl]oxy}pyridin-2-yl)piperazine- 1-carboxamide

244 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)-N-[3,5- bis(trifluoromethyl)phenyl]piperazine-1- carboxamide

245 4-(3-{[1-(2-aminopyrimidin-4- yl)ethyl]oxy}pyridin-2-yl)-N-(3-ethylphenyl)piperazine-1-carboxamide

246 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}-6-chloropyridin-2-yl)-N-(5-ethyl-2-fluorophenyl)piperazine-1- carboxamide

247 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-(3-ethyl-5-fluorophenyl)piperazine-1- carboxamide

249 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3-chloro-2-fluoro-5- (trifluoromethyl)phenyl]piperazine-1- carboxamide

250 4-(3-{[(2-aminopyrimidin-4- yl)methyl]oxy}pyridin-2-yl)-N-[3,5-bis(trifluoromethyl)phenyl]-N- methylpiperazine-1-carboxamide


26. A pharmaceutical composition comprising the compound according toclaim 1 and a pharmaceutically acceptable carrier.